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Alzheimer’s: Prevention from childhood
Félix Bermejo-Pareja
Director of the Extraordinary Chair in Alzheimer’s, Faculty of Medicine, Complutense
University, Madrid. Emeritus Professor of CIBERNED, Madrid. Senior consultant neurologist of research at Imas12, Madrid.
Spanish text revised by science journalist, Sonia Moreno.
Translation into English by Joe Haley and Félix Bermejo Pareja. i

ii

There is no longer room for preventive nihilism .
Albert Hofman, epidemiologist iii

iv

Prologue ............................................................................................................................................... vii
Spanish edition presentation .................................................................................................................. ix
Preamble of the Spanish edition ........................................................................................................... xii
English version presentation ...............................................................................................................xiii
Main Abbreviations ............................................................................................................................. xiv
1. Is the title of this book exaggerated? .................................................................................................. 1
2. Is it true that Alzheimer’s disease can be prevented? ......................................................................... 3
3. Convince me that Alzheimer’s can be prevented. ............................................................................... 7
4. Isn’t Alzheimer’s a hereditary disease? ............................................................................................ 10
5. Does Alzheimer’s disease begin in old age?..................................................................................... 13
6. A little (very little) about neuroanatomy and the functioning of the brain ........................................ 16
7. Cognitive reserve: an important reserve, but what is it? ................................................................... 29
8. How has it been found that Alzheimer’s starts before dementia appears? ........................................ 34
9. Why population-based studies? What are they? ............................................................................... 38
10. Risk and protection factors. Causality in complex diseases. ........................................................... 41
11. The genetics of Alzheimer’s disease – understandable and not too difficult .................................. 44
12. Historical note: a psychiatrist called Alzheimer and his generous boss .......................................... 51
13. Does Alzheimer’s always start with a loss of memory? ................................................................. 55
14. How does this disease progress and how does it end? .................................................................... 60
15. Preclinical, prodromal and pre-symptomatic Alzheimer’s. What are they? .................................... 64
16. Is Alzheimer’s really going to increase as much as the prophets of doom say? .............................. 68
17. What tests are necessary for diagnosis? .......................................................................................... 72
18. What is Alzheimer’s? Exaggerated ageing? Complex disease? Neurodegeneration? Or don’t we know what it is? ................................................................................................................................... 76
19. Is it that unlikely that there will be medications to cure Alzheimer’s? ........................................... 80
20. Are memory exercises any use? ..................................................................................................... 86
21. If curative therapies fail, is prevention the only option? ................................................................. 90
22. Prevention: start at the beginning ................................................................................................... 95
22A. Does the family of the future child have anything to do with Alzheimer’s? ............................ 95
22B.The prenatal period – be careful during pregnancy ................................................................... 99
22C. Childhood and youth: we have to get the sapling to grow straight ......................................... 104
22D. Does the risk of Alzheimer’s arise in adulthood? .................................................................. 109
22E. Don’t ignore old age .............................................................................................................. 113
23. Risk and protection factors in Alzheimer’s disease ...................................................................... 120
23A. Ageing ................................................................................................................................... 122
23B. Education and cognitive reserve ............................................................................................ 127
23D. Physical exercise is always required ...................................................................................... 130
23E. Is there any better diet than the Mediterranean diet? .............................................................. 133
23F. More risk and protection factors – or only associations? ........................................................ 137
24.Conclusions: prevention of Alzheimer’s from childhood .............................................................. 142
Bibliography section .......................................................................................................................... 147
Glossary
*
............................................................................................................................................ 222
Acknowledgements ............................................................................................................................ 235
Index .................................................................................................................................................. 237 v

vi

“Know to foresee, foresee to prevent.”
Coming to know and deciphering the symptoms of molecular alterations, from childhood if possible, allows the adoption of measures that correct or mitigate the usual trajectory of this neuropathy, which is progressively more frequent, also due to increased longevity.
This is a monograph of scientific dissemination. After his retirement as a clinical neurologist,
Dr. Félix Bermejo has worked as a researcher of chronic neurological diseases and in neuroepidemiology, as Professor Emeritus and an Extraordinary Chair in Alzheimer’s and neurodegenerative diseases in the Faculty of Medicine of Complutense University in Madrid.
First of all, to set the context. To do this, the book tackles “disease and aging in modern society”. The hygienic and sanitary measures increasingly adopted worldwide, to a greater extent in the most developed countries, in effect, have permitted the extension of the normal human life. This has meant that neurodegenerative diseases have themselves increased progressively.
Particularly interesting is the answer to the question “How has it been found that Alzheimer’s starts before dementia?”. Together with the clinical aspects, what are very important are the data referring to molecular alterations that can be detected with the modern tools of physical introspection, at the very early stages of onset.
Another chapter that stands out particularly is the one that investigates “causality” in complex diseases, since nowadays it is clear that each human being is unique at every moment in his life from the biological point of view, but also intellectually and culturally. “Identities” that are pathological and mental are being understood increasingly deeply, permitting the establishment of relationships and discrepancies between diverse disorders, whose diagnosis allows us to recognise similarities and differences in the causality of numerous diseases.
The author also devotes time, with great teaching skill, to the individual features of preclinical, prodromal and presymptomatic Alzheimer’s. These are all characterised by a different degree of neuronal damage which, generally gradually, leads to irreversible situations.
Having described the physiopathology in accessible terms and having considered its possible prevention, the author goes on to describe the risk and protection factors. The appreciation of the latter allows – and will allow much more in the future – us to attenuate or counteract risk factors, especially those of vascular nature.
Obviously, physical exercise, diet, appropriate education, etc. are analysed in this easy to read volume which, I am sure, will allow us to orient ourselves better and to establish more suitable perspectives for the prevention, as far as possible, of Alzheimer’s from childhood
“and throughout life”.
There is no doubt that neuropathies such as Parkinson’s, Parkinsonism, Alzheimer’s and other neurodegenerative disorders are now providing data that will not only allow future palliative vii

treatments, but will also, above all, allow active prevention. Increasingly, medicine will be personalised, and this will be aided by the development and perfection of diagnosis tools, as well as knowledge of genetics and, above all, epigenetics. This is about regulation mechanisms of extraordinary, marvellous complexity. If the main benefit is the health to be able to fully use the distinctive faculties that set humans apart, we should invest all the appropriate financial, personal and technical resources therein. This is because if “all human being have equal dignity”, then medical advances must be applied to each and every one of them, especially those relating to the workings of the mind, the faculty that is exclusive to the mystery of human existence.
Federico Mayor Zaragoza
25 October 2016 viii

The reader who decides to delve into the contents of this book does so starting from the two basic concepts contained in the title: Alzheimer’s disease and prevention. For that reason, it is not unreasonable to begin this presentation with a few brief comments about them.
Regarding the first of these terms, Alzheimer’s disease, it is worth remembering that from the first description of the disease at the beginning of the 20 th
century, it has been markedly on the increase, even more so in recent decades, in parallel with the continual expansion experienced in the last half century. Currently it is considered one of the health epidemics which has not been overcome that ranks with – or even above – other important chronic processes such as diabetes, obesity and osteoporosis. Today it is, without doubt, one of the great epidemics of the 21 st
century.
This has been exacerbated enormously, at least in epidemiological terms, by the spectacular aging of the population, maintained throughout the last century. But many other factors have contributed, of which perhaps one of the most meaningful is determined by the limitations in our understanding of the disease. This is a challenge that has not been overcome in very many aspects, above all regarding the paucity of efficacious therapeutic techniques that cure or alleviate the symptoms of those suffering from the disease. In practice, we are dealing with a universal health problem, which today is irreversible, that has transcended the limits of medicine and has entered squarely into the realm of the concerns of civil society, going so far as to become a daily topic in the most diverse mainstream media.
As stated in one of the first chapters of the book, “Public health is not only a matter for doctors, but rather for all of society and all people.” Evidently, today, Alzheimer’s disease is a serious public health problem whose dimensions pass the limits of the patient himself and that extends to all those related directly or indirectly with each sufferer. This is a problem that exceeds the capacities of health administrations and means that any attempt at a solution must always be integrated in a global package.
An idea of the importance granted to this subject is given by what has been created around it: scientific societies, specific publications, all kinds of working groups, research projects financed by the main private and public agencies, victims’ and relatives’ associations, and endless initiatives. All these initiatives are oriented to advancing our knowledge, a task that is proving extraordinarily difficult, with advances coming more slowly than in other areas of medicine. In the area of Alzheimer’s today, there are still far more questions than answers.
The concept of prevention, the second part of the title, has always been key in medicine, and this is becoming ever more true nowadays. Also, it has long since passed from the strictly medical ambit to forming part of popular wisdom. “It is better to prevent than to cure” is a saying that has existed for more than a century and, as with all sayings, belongs to ordinary folk and is recorded on the hard disc of every person. Assessing and enhancing the consequences of its application to the disease analysed here is, undoubtedly, the primary aim of the author.
In medicine there are two basic principles on the subject of prevention. The first, unarguably, is made explicit in the title and will guide the whole content of this book. It alludes to, “the ix

sooner the better” – in health terms, any form of prevention must start from day one, in some cases even before birth, during pregnancy. This principle is universal in medicine and thus applies to Alzheimer’s disease, as we shall see.
The second principle, which should never be forgotten, and which geriatrics professionals stress, is that it is “never too late to prevent”. There is no upper age limit. Developing this second principle is not one of the specific stated aims of this book but it is always worth remembering it and knowing that also for different issues related to Alzheimer’s disease it is possible to establish preventive measures, whatever the age of the patient and the state of evolution of the process. This is also mentioned in some of the chapters.
We have before us a book whose main aim is to inform: to answer rigorously the numerous questions that come up every day; to do so in a clear, accurate and objective way, ambitious in its selection of content and concise in its presentation. The author achieves all this with integrity and drawing on the professional experience of one who has spent a lifetime fighting this disease and teaching the subject. In short, we have here a book that aspires to become a health education tool within this field.
This is a book that aims to reach and make itself accessible to a very wide range of potential readers: from the health professional – doctor, nurse, pharmacist, psychologist, social worker etc. – who, although not a great expert on the subject comes up against it on a daily basis, to any other person who, for whatever reason wishes to be up-to-date with the most basic elements of this process and to have an adequate tool to answer the questions that may come up. This second group includes acquaintances or relatives of victims of the disease, health information professionals, educators and (why not?) the vast number of people who, from mere intellectual interest, would like to improve their knowledge on the subject of health.
Bearing this in mind, it is important to point out that this book includes a first rate collection of complementary material. In many cases there are footnotes commenting on particularly significant events or biographies. Also, there is an extensive, very up-to-date bibliography with hundreds of citations, which includes works ranging from those of a general nature to reviews and original articles by those researchers who have contributed most to defining the boundaries of our current knowledge. This means that every reader, at whichever level, has the chance to deepen their knowledge of what interests them most.
The very extensive table of contents is ambitious and the book goes way past the notion of popularisation of science which usually inspires this kind of monograph. In my opinion it is much closer, due to the rigour with which each chapter is written, the subjects chosen, the methodology followed and the currency of the collected concepts, to what we could call a scientific book. The chapters are concise and clear in their approach. They are reasonably well ordered and leave the reader with the sensation of having found, in each case, a good answer to the questions that led him to tackle the chapter. Each chapter is basically short, well-written and generously didactic, and aims to answer one of the key questions that any person, expert or not, might ask in relation to Alzheimer’s disease. To my mind, as a whole, they cover the vast majority of questions that can be asked on this subject – obviously, without any doubt, the most important and frequent ones. x

Some final comments about the author: without going into detail, or aiming to summarise his
CV, it is worth stating that D. Félix Bermejo is one of the most prestigious and acclaimed neurologists in Spain. His work over the last four decades in “12 de Octubre” Hospital, directing the neurology service in the latter part of this period, corroborates this statement. He has been president of the Spanish Neurology Society and has held various relevant posts in his area of speciality, both in Spain and in international organisations. His teaching and research work, a good part of which has revolved around Alzheimer’s, is widely recognised in the world of medicine. This work has been translated into several hundred scientific publications.
He has been the supervisor of numerous doctoral theses in this area and has assiduously attended pre- and post-graduate courses and training days – he is passionate about teaching.
For years he chaired the corresponding committee in his hospital.
In my opinion, it is only through the experience accrued from a rich career of this nature and from the unwavering enthusiasm for the dissemination of knowledge and the improvement of the health culture, that one can tackle the challenge of writing a book such as this.
Enthusiasm, knowledge, determination and experience are the fundaments that are hidden behind the quality of the messages conveyed. Dr. Bermejo has clearly shown with this work that he is in possession of all these virtues, to a high degree.
José Manuel Ribera Casado
Emeritus Professor of Geratrics at Complutense University, Madrid
Full Member of the Spanish Royal Academy of Medicine xi

Providing adequate care for the patient with dementia or Alzheimer’s is becoming more and more difficult and costly in our society a
. This difficulty, together with the aging population has led to somewhat exaggerating the situation. The media participate in this exaggeration, increasing the number of cases (in Spain it has been said on TV that there are more than a million, which is untrue...), and the importance of discoveries and therapies for this affliction b
. But it is also true that the general and specialist press, and patient associations have disseminated many aspects of Alzheimer’s over the last three decades and have contributed to its understanding. However, in recent years, faced with the failure of anti-amyloid therapies to cure or detain the disease, the need for active prevention, prior to the appearance of a pathology that has no curative treatment, has increased. Given the minute probability, with current knowledge, of finding an (almost magical) therapy soon that eradicates Alzheimer’s, it is reasonable to focus on its prevention, which does not require such huge outlays as those necessary for its basic research or the development of medications. This attitude is not the wish of desperate scientists, but rather a premise that is rational and substantiated by experts c
.
Alzheimer’s can and must be prevented, independently of curative drugs (if only!). This monograph aims to spread this message, using simple language where possible, and in chapters that can be read in isolation. Care has been taken with the biomedical terms (with abbreviations to reduce the text) and there is a glossary to aid comprehension d
. Interested readers can broaden their knowledge reading the footnotes e and there is an extensive bibliography. Some real clinical case have been described (modified to avoid recognition) to clarify clinical concepts. The description of factors that increase the likelihood of the appearance of Alzheimer’s (risk factors) and those that delay it (protection factors) are accompanied by explanations of their biological basis and practical measures for their control.
This will mean visiting the population-based studies – an exciting scientific method which, today, forms the basis of the recommendations for a healthy lifestyle. a
T he concern for Alzheimer's extends from supranational institutions ( Global Action Against
Dementia : G8, 2013; OECD, 2013; WHO, 12; Shah et al, 2016 ) until professional and scientific associations ( Winblad et al, 2016 ). b
These exaggerations have been written in the New York Times and sums them up Lock, 2013; pp:
93-99.
On the other hand, the knowledge of the general population on the Alzheimer prevention of is scarce ( Cations et al, 2018 ).
c
Examples of recent professional articles about dementia and AD prevention: Dehnel, 2013 ; web of
European Dementia Prevention Initiative (http://www.edpi.org); Smith & Yaffe, 2014 ; Khachaturian
& Khachaturian, 2015; Corriveau et al, 2017 . In Spain: Bermejo-Pareja et al, 2010, 2016. d
The text incorporates footnotes (FN) that explain with references the scientific explanations of the text statements. The references that FN includes can be consulted in the Bibliography section. At the end of the text, there is a glossary of biomedical terms to facilitate the comprehension of some difficult terms because this monograph is designed with informative intent. e
Nota bene. The references are writing in italics in the FN with the exception of exposed after a dot; the authors in Harvard style. In the Bibliography section, the references are writing in AMA style by author’s alphabetical order .
xii

The Spanish version was finished in March 2017 and was published in July 2017 (by AACI,
Madrid). The English version is a re-write by Joe Healey (native English speaker and English teacher in Spain) and Félix Bermejo-Pareja, the author of the Spanish work. After the kind invitation of Ms Alina Covali from the publishers LAP Lambert, we began the English version in September 2017.
The English version is quite similar to the Spanish version in that it aims to be an accessible text with scientific data (mainly presented in the footnotes).
The English version alters the reference and the footnote style (by Chapters in the Spanish version and continuously numbered in this edition). Some new references were incorporated in this text and others were discarded (mainly the references and footnotes with only specific interest for Spanish readers).
In this edition, very few chapters were modified slightly and only one was completely rewritten (Chapter 11). The English version includes the majority of tables and figures in the
Spanish version, but in black and white, and includes two new figures designed by JM Gibert and J Ramos.
Félix Bermejo-Pareja and Joe Healey
April 5, 2018 xiii

AD: Alzheimer Disease
ACI: Acetylcholinesterase inhibitors (anti-Alzheimer drugs)
ADI : Alzheimer Disease International
AHRQ: Agency for Healthcare Research and Quality
AMA : American Medical Association
ApoE4 : Apolipoprotein E4
APP: Amyloid precursor protein
$ ȕ
: Amyloid-beta
BADL : Basic activities of daily living (e.g., to eat, to clean oneself up)
BMI: Body mass index
Chap : Chapter
CPG : Clinical practice guidelines
CogR: Cognitive reserve
CNS: Central nervous system
CSF: Cerebrospinal fluid
CT: Computed tomography (cerebral scanner)
CVD : Cardiovascular disease/s
CVRF : Cardiovascular risk factors
Dpt.: Department
DM2: Diabetes mellitus type two
DNA : Dexosy-ribonucleic acid
DOHaD : Developmental Origins of Health and Disease
DSM: Diagnostic Statistical Manual (see Glossary) fAD familial AD (monogenetic AD)
EMEA : European Medicines Agency (EU agency for drug approval)
FDA : Food and Drug Administration (US agency for drug approval)
Fig : Figure xiv

fMRI: functional MRI
FTD : Frontotemporal dementia (previously Pick disease)
H.: Hospital
HBP : High blood pressure
I.
: Institute
IADL : Instrumental activities of daily living (e.g., phone use, count money)
LBD : Lewy body disease
MCI: Mild cognitive impairment
MeDi : Mediterranean diet miRNA : MicroRNA
MMSE: Mini Mental State Examination
MRI: Magnetic Resonance Image
NCB: Neurología Clínica Básica; Neurological text of the UH12O ( see Bermejo-Pareja et al.
2012 )
NCD: Non-communicable diseases
NDD : Neurodegenerative disease/s
NEDICES: English acronym of the Neurological Disorders in Central Spain (Population based survey of the UH12O Dpt. of Neurology)
NFT : Neurofibrillary tangles
NFD : Neurofibrillary degeneration (NFT, NP, and neuropil threads)
NIA : National Institute on Aging (USA)
NICE : National Institute for Clinical Excellence (UK)
NIH : National Institutes of Health (USA)
NP : Neuritic plaques (senile plaque with NFT)
NPT: Non-pharmacological therapy
NS: Nervous system
NSAID : Non-steroidal anti-inflammatory drugs
OR : Odds ratio (see Glossary)
PD : Parkinson disease xv

PhA : Physical activity
PAR : Population attributable risk (see Glossary)
PET : Positron emission tomography
PF: Preventive factor
RF : Risk factor/s
RNA : Ribonucleic acid
RR: Relative risks (see Glossary) sAD : sporadic AD
SES: Socioeconomic status
SP: senile plaque
SPECT: Single photon emission computed tomography
TDP-43: TAR DNA-Binding Protein 43 (see Glossary)
U .: University
UH12O: University Hospital “12 de Octubre”. Madrid
VaD : Vascular dementia
WHO: World Health Organization xvi

The statement that gives the title to this book may seem provocative or exaggerated, but it is not. In fact, it does not go far enough. The risk of Alzheimer’s disease (AD), as with other chronic pathologies, such as cardiovascular diseases (CVD) and diabetes in the elderly, can develop in the womb. Poor foetal nutrition induced by the poor diet of the mother, the consumption of tobacco and alcohol during pregnancy, and low birth weight create a disposition to the diseases, to mention a few of the influencing factors. It might be surprising that Alzheimer’s, considered a disease of old age, has its origins or risk factors dating from birth. In addition, to add to this surprise, this is a consequence of scientific advances. From the 60s to the 80s, research into AD was confined to clinical or pathological studies of patients with this disease. From then until the end of the millennium, we began to become aware that AD is an affliction that starts in the brain in middle age (or even in early adulthood). Finally, in the new millennium, the data that began to emerge at the end of the 80s were confirmed – that pointed to the foetal (and childhood) origin of many adult diseases
1
.
It was two British researchers, whose conclusions gave rise to the name of what is known today as the Barker or Barker-Osmond
2
hypothesis, who established this origin. Barker, a doctor and epidemiologist at the University of Southampton in England, and his team carried out an ecological study : they analysed infant mortality in England and Wales and death from myocardial infarction. They found a high positive correlation between the two (the higher the infant mortality, the more deaths from myocardial infarction occurred) and they posited that the cause of both events was poor nutrition in the first years of life. The fact agreed with what was observed in poor immigrants from India who arrived in England. They found that the hypothesis that related poor infant nutrition with an alteration in biological development had already been described in 1909
3
. However, they did not stop there, but rather they persisted with their research. They reviewed the medical histories of English children in several counties, where data such birth weight and the circumference of the head were given, and they collated the data with the information in the Deaths Register, which reported deaths and their causes. In this way, they determined that low birth weight was a clear risk factor of cardiovascular mortality. Obviously, this finding does not mean that there cannot be premature or low birth weight babies who are free from complex diseases , such infarction, diabetes or AD, and who apart from boasting perfect health are intellectually brilliant. What
Barker and Osmond proposed is that those born in unfavourable conditions (such as poor maternal nutrition) have more risk of suffering from certain conditions. This relationship has
1
See comments about dementia ( Whalley et al, 2006, 2015 and Gluckman & Hanson, 2006) in relation to many chronic disorders or non-communicable diseases (NCD) .
2
The British epidemiologist, David Barker, and the statistician, Charles Osmond, were the first authors to launch the hypothesis of foetal hypo-nutrition and low birth weight as an RF for CVD mortality and morbidity ( Barker
& Osmond, 1986; Barker et al, 1993 ) by means of ecological surveys. After that, Barker and his team performed more investigations (Hertfordshire cohort in UK and others) showing that foetal hypo-nutrition was related to several CVD and NCD. Other cohort surveys (Aberdeen cohort, Lawlor et al, 2005; Helsinki cohort, Kajantie et al, 2005) confirmed his findings ; In Chap # 10, the reader will understand how this hypothesis has added new studies over time and has turned into the D evelopmental O rigins of H ealth a nd D isease, (DOHaD) . Currently,
DOHaD, has a scientific society and journal (www.dohadsoc.org)
3
Baker & Osmond, 1986, cited Chapin, 1909, as a precursor of this idea.
1

been confirmed in new studies and has been extended to other disorders, primarily high blood pressure, diabetes, metabolic syndrome, osteoporosis and AD
4
.
The hypothesis, also known as early foetal programming of adult diseases, is accepted, although some prospective studies have played down its importance. This common criticism led to the modification of the initial premise, and after numerous studies, we have arrived at the certainty that the earliest life situations (prenatal and the first postnatal years) are important in the future development of many chronic illnesses (as if in its first experiences, the child were preparing itself for future life). It has also been observed that this predisposition could be transmitted from parents to child not through the DNA (genes), but rather through epigenetic mechanisms ( soft inheritance ) and be part of the process known as intergenerational transmission
5
. In a later chapter, the meaning of these (fairly unknown) concepts will be discussed.
This book also looks to remind people that public health is not only a matter for doctors
(which it is), nor for society as a whole (including habitat). It also includes the individual care of one’s own health: avoiding risks and endeavouring to have an attitude of protection from diseases (for example, not smoking) starts very early, as early as in the uterus, and even before, in the family. This is why mothers who look after their health have healthier children at birth, and throughout their lives. The sapling must not grow crooked. We will see how a happy infancy and careful infant education contribute to health in adulthood and old age, and strengthen the brain – exactly what is injured in Alzheimer’s disease.
4
Several authors maintain the origin in foetal life and infancy and throughout life of many adult diseases, mainly complex disorders and NCD ( Ben-Shlomo & Kuh, 2002; Yankner et al, 2008; Wadhwa et al, 2009 ), and dementias ( Whalley et al, 2006, 2015 ) and AD ( Borenstein et al, 2006; Faa et al, 2014; Knuesel et al, 2014 .
5
See Brook et al, 1999; Saben et al, 2016; Brown, 2016 .
2

Obviously, there will always be sceptics – even those who question medical texts or the efficacy of medicine
6
. But, if we do not take an extreme position, we should review the medical literature and, judging by the scientific publications of recent years, the unbelievers are in the minority. A first well-founded article appeared at the turn of the century; since then the interest in researching the prevention of dementias and AD has not ceased to grow. See figure 1 (2.1), which depicts the increase in publications in Medline, a database with the biomedical studies gathered by the U.S. National Library of Medicine
7
.
Figure 1. (2.1).
Publications on AD prevention in Medline *
See the number of article increase in the last 10-15 years *Data obtained from www. pubmed.com
(April 2016).
It is true that perhaps most people think AD is something belonging to old age, and that in a street survey people would classify it as genetic. These assertions have some truth in them, but much more untruth.
To summarise, about 1% of AD cases are familial (fAD) and genetic; this is dominantly inherited due to gene anomalies (there are three genes whose alteration is known to produce fAD). Families that suffer from this form of the disease are usually aware of it, because of the family history (grandparents, parent, siblings or aunts/uncles of the patient). Nevertheless, the vast majority of cases, more than 95% of disease cases are sporadic (sAD), appear in old age, above the age of 75, and have no identifiable genetic determination
8
.
6
Not only homoeopathists or other pseudoscientists, but also other authors such as Ivan Illich , who in his book
(1975) maintained that the doctor’s medicine harms more than cures.
7
It can be obtained from www.pubmed.com
; here there are more than 28 million abstracts from selected biomedical journals and books, completely free of charge.
8
Bekris et al, 2010, analyse fAD and sAD frequency. See Chap # 4 and # 11.
3

sAD, also called non-familial, idiopathic or primary Alzheimer’s, is complex. As with all diseases of this type, whether it is cancer or diabetes mellitus, to mention two frequent examples, both genetic and environmental factors have an influence. AD must not be considered a genetic disease in the strict sense, although this does not exclude the intervention of genetic risk alleles such as allele E4 of the ApoE gene and protectors (ApoE2) as well as dozens of other genes, each one of which has a small causal or risk contribution
9
. Without excluding the intervention of genes, a large part of the risk of sAD comes from environmental exposure. That is to say, the conditions that have surrounded an individual throughout his life, starting from birth – the womb is the first environmental determinant – and continuing with education, physical activity, food, contact with toxins (pesticides in rural areas; air pollution in urban areas), to mention but a few.
Regarding blaming age... well, yes and no. Age is the main risk factor of AD, which increases exponentially as we age, with the prevalence (frequency) over the age of 90 reaching about
40-50%. Nevertheless, many people do not have the disease even though they are over 80, 90 or 100. It is not that they are just OK cognitively – they continue to carry out their activities with great success. Picasso was still painting past the age of 80. Goethe completed Faustus also as an octogenarian, and the Nobel Prize winner Rita Levi-Montalcini continued working in her laboratory practically up to her death at 103
10
. That is to say, aging makes the appearance of sAD more likely, and this is why it was known as Alzheimer’s senile dementia .
Nevertheless, age seems not to cause the disease, but rather to contribute to it.
“So what are the processes that make it more likely?”
As we have said, genetic inheritance makes it more likely. Some scientists note that the genes we inherit from our family represent 48% of the risk of the disease; for others this percentage is not so high (30%), while there are those who believe the figure to be as high as 60%
11
. In reality, the exact percentage is not known and probably varies from person to person. Be that as it may, inheritance is hard to modify, although there are epigenetic mechanisms
12
that can turn on or off (change) the expression of certain genes (i.e. activate them or prevent them from acting). Besides, biological age is not the same for everyone: some appear young at 70
(especially if they have dyed hair). Likewise, a physically or mentally active lifestyle can delay what we normally call old age. But these two clear risk factors (genes and age) cannot be modified (for the moment; no doubt in the future it will be possible), nor, of course, can they be prevented
13
. Sex cannot be biologically changed either, and this might be an RF of sAD for women, although this is not clear
14
.
9
The gene ApoE contains four alleles (four formations). The allele ApoE4 transmits an increase of AD risk
( Ward et al, 2012 ) and the ApoE2 allele decreases AD risk ( Raber et al, 2004 ).
10
There are many examples of the increase of human survival (from 1750, James Vaupel, 2010 demonstrated this fact). Many aspects of Spanish ageing (second country in the world, after Japan, in life expectancy) were discussed in Blasco & Salomone, 2016 (See FN # 268). An anecdote: one Spanish nonagenarian, an old republican fighter pilot of the Civil War studied, at the age of 90, History at university, and when over 100 wrote his memoirs ( Agudo, 2016 ).
11
12
See Pedersen et al, 2004, for an interesting review of the subject.
13
In Chap # 11 a discussion of AD genetics and epigenetics is given.
14
See Wang et al, 2013, review of AD and ageing relationship, and also Chap # 11.
The prevalence of AD is higher in women than in men, but the great survival of old women could be the explanation. See the debate in Chap # 23.
4

In brief, sAD is considered a complex disease in that risk and protection factors are involved, both genetic and environmental, and throughout life
15
. The result of all these usually manifests itself in senescence , as old age increases the time of exposure to internal and environmental noxas, and can be very long (and will become increasingly more so). Table 1
(2-1) has a list of risk and protection factors – an appetizer for what will be described in this monograph. At first sight, this table may seem very long, and it is – it is no illusion. But it is better to start the description as a complex subject and later we will see that is, in fact, not so complex.
Table 1 (2.1).
Main risk factors (RF) and prevention factors (PF) for sAD &.
Classification according to the possibility of risk modification
Risk Factors
Non-modifiable
Person : Age, sex
Parents : Low maternal (< 8 years) and paternal education, large family (> 7 siblings)
Mother : Low education, inadequate nutrition status, diet and lifestyle
Genetics : ApoE4 and other infrequent alleles; family history of dementia
Partially modifiable
Epigenetics: Genes-environment interaction risks (not well known)
Modifiable
Foetal: Hypo/hyper maternal nutrition, prematurity, toxic exposure (tobacco)
Infancy & adolescence: Low education, low SES (poverty), frequent infections
Adulthood: CVRF (hypertension, obesity, DM2 and others).
Old age : Social isolation, frailty
Lifestyle : Toxic habits (tobacco, alcohol, illicit drugs), unhealthy diet, sedentary
Illnesses : Severe head trauma, bad health?, depression?, some infections?
Biological: Inflammations, immunological disorders
Miscellaneous : Sensory deficits (blindness, deafness)? , social isolation
Environmental toxins : Pesticides, occupational toxins (metals), air pollution
Protective Factors
Non-modifiable
Family members & parents : Good maternal education, agreeable emotional & intellectual atmosphere
Genetics: Protective genetic alleles (ApoE2 and two more)
Partially modifiable
Epigenetics: Genes-environment interaction risks (not well known)
Modifiable
Foetal RF: Happy pregnancy*
Infancy & adolescence: Maternal breast-feeding; education, adequate nutrition and PhA
Adulthood & old age : Absence of CVFR, continuous intellectual and PhA, social interaction
Nutrition : Healthy diet (MeDi and others), omega-3 fatty acids, coffee and others?
15
See Whalley et al, 2006, 2015.
5

Good mental and physical health
Absence of environmental and personal toxics (excess of alcohol, tobacco and so on)
& Summarized with data of several authors: Whalley et al, 2006; Anstey et al, 2015; Baumgart et al,
2015; Sindi et al, 2015; Xu et al, 2015 a; Bermejo-Pareja et al, 2016 b; Livingstone et al, 2017
Abbreviations. PhA: Physical activity; SES: Socioeconomic status; CVRF: cardiovascular risk factors; DM2: diabetes mellitus type 2 (adult DM); MeDi: Mediterranean diet
* Happy definition of good pregnancy
To close this chapter, it must be stressed that a rigorous education, physical activity (many children do not do it) and adequate diet become the foundations for protection from
Alzheimer’s. It is likely that half of the cases of sAD have risk factors which can be acted upon, thus delaying its appearance
16
.
16
Many authors ( Barnes & Jaffe, 2011; Beydoun et al, 2014; Norton et al, 2014; Anstey et al, 2015; Baumgart et al, 2015, Bellou et al, 2016; Livingston et al, 2017; Lafortune & Brayne, 2017) analyse the RF and PF and the proportion of modifiable RF. Nevertheless, it is very difficult to set up RCT to demonstrate the efficacy of AD prevention ( Coley et al, 2008; Sachved, 2009; Kane et al, 2007 ).
6

Well, people accept more things that are incredible. Humans have always been very credulous. The ancients thought the Earth was flat (the Greeks and educated Medieval people, a tiny minority, did not), and that at the horizon, the sky and sea were stitched together. The
Greeks also believed in the divination of the future by oracles, who supplied them with ambiguous sentences where the positioning of a comma could change the meaning. Not only did they have to divine the future, they also had to divine what the diviners were predicting.
And, despite this, ancient Greece was the cradle of democracy and Western thinking. These days, most newspapers publish a daily horoscope and many people think what they say can affect them. However, how can an identical prediction be accurate for a twelfth of the population? Many people think like that, faced with hope for and fear of the future. This book does not aim for credulity; science is the search for truth, using rational and convincing mechanisms – this is what we are doing.
The data we have are the following: the first is bibliographical – what we saw in figure 1
(2.1). Who can defend the opinion that something is untrue (the prevention of Alzheimer’s) when in the last decade more than 300 scientific articles have been written about it every year? It’s unlikely that so many scientists are befuddled and are investigating something senseless. Also, the World Health Organisation (WHO) and other medical associations and scientists who advocate it... could they are wrong? Of course, they could, as it has happened before. But, could the WHO, various scientific associations, and a plethora of scientists and doctors really be wrong? It is possible
17
, but highly unlikely...
In order to accommodate the sceptical arguments as well, we shall cite a publication produced by a Task Force , which is a meeting of experts, in this case sponsored by the National
Institutes of Health (NIH). They analysed the prevention of sporadic Alzheimer’s (sAD) and concluded that there was no definitive proof of many of the proposed protection factors (PF), such as physical exercise and diet, among others
18
. The validity of many of the suppositions in Einstein’s theory of relativity, such as the speed of light and gravitational waves took many decades to confirm, and we witnessed the verification of the Higgs boson in CERN,
Switzerland, many decades after the postulation of his theory. At least Higgs was alive to see its discovery confirmed. However, the caution of the American Task Force wavered seven years after publication, with the data collected in the last five years, which have produced new
17
Taleb’s monograph (2008) pointed out the possibility of incredible facts in the sphere of social sciences, but in the biomedical sciences the incredible (biologically unacceptable), is very unlikely to occur.
18
Williams et al, 2010 (USA Federal Agency, AHRQ) , reviewed 6,713 papers about prevention of cognitive decline, dementia and AD. Their final statement was that there was not high evidence for the majority of behavioral (and lifestyle) protection factors against AD. The best scientific evidence is obtained by randomized control trials (RCT), which are very difficult to perform in this field. The long pre-symptomatic period of AD requires longstanding RCT, which are almost impossible to carry out. However, the absence of the best grade of scientific evidence does not mean that there was no evidence at all. Well-designed prospective cohorts also have great value to demonstrate preventive measures against dementia and AD ( Kroke et al, 2003 ). In 2017, the same
Agency (AHRQ) reviewed the data again (Kane et al, 2017) and arrived at an analogous conclusion, considering physical activity the most promising PF against dementia to reach high evidence. The methodological problems in this scenario are the need for long follow-ups and lower attrition. In addition, the USA National Academies of
Sciences (Leshner et al 2017 ) released a slightly more optimistic document promoting physical activity, HBP control and cognitive training to fight against AD.
7

findings (in population-based epidemiology), even though we still need random clinical trials to confirm them
19
.
Not everyone has been as lucky as Higgs. The confirmation that scurvy is caused by a lack of vitamins did not happen until well into the 20 th
century (vitamins were discovered starting from 1928 but there was already proof that sailors who ate fruit and lemons did not suffer from it). It has been said that scurvy killed more English seamen than the French and Spanish navies combined
20
. 50 years passed before the Royal English Navy made it compulsory for the crew to eat lemons on long voyages. Other examples could be given: cholera and tuberculosis had declined markedly at the end of the first third of the 20 th
century due to improvements in hygiene and nutrition, before the introduction of specific antibiotics. The reduction of tobacco consumption has been one of the causes of decreased mortality from myocardial infarction.
In addition, more evidence appears every day that shows that the prevention of sAD is possible. The European Union has promoted prevention trials for this disease. The opinion leaders of American biomedical research also see the situation this way
21
. They believe that prevention seems to be the most practical way to advance and the path with the most likelihood of getting results in public (and individual) health. Of course it is considered more efficient than the huge and costly basic research into this disease, which despite increasing our knowledge enormously, has not generated the bases for the production of drugs that prevent or delay its appearance. There are already data that indicate that in the developed countries there is a decline in dementia and Alzheimer’s. The measures aimed at improving education, decreasing physical inactivity, reducing vascular RF and increasing the quality of diets, for example, are producing a reduction in the incidence and prevalence of dementia and AD
22
.
Two important studies
23
came out in 2016: new data gathered from the very well-known
Framingham cohort, a population group who researchers and epidemiologist have been following for decades, reveal that the incidence (new cases) of dementia is lower in recent years than it was 30 years ago, when the presence of dementia was first studied.
For the stubborn non-believers, more proof will be presented in the following chapters. But, for now, it is enough to say that researchers have gone so far as to calculate how much the prevalence and incidence of dementia and AD could be reduced. The reduction could be
19
Baumgart et al, 2015, reviewed the dementia RF in population-based surveys.
20
The history of scurvy is fascinating. This old disease caused by vitamin C deficiency was an epidemic among sailors in the long transoceanic voyages over several centuries from the 15th century, with diets including very little fresh food. However, Vasco da Gama (1470) and his sailors knew that lemons relieved scurvy symptoms.
In the 16th century, Spanish sailors were cured from scurvy in Mexico by lemons, oranges and limes. However,
British doctors (James Lind, 1747, and his crew) were the investigators who demonstrated by simple experiments the preventive effects of citric juice and fresh food. Many decades later, the British Navy ordered a compulsory diet of lemons for every sailor ( Baron, 2009 ).
21
Several international institutions (WHO) and the European Dementia Prevention Initiative (EDPI; www.edpi.org) promote studies and preventive RCT against dementia and AD ( Dehnel et al, 2013 ); some of them have promising initial results ( Ngandu et al, 2015). In addition, opinion leaders promote this fight ( Smith &
Yaffe, 2014 ) as well as other documents ( Lock, 2013; de la Torre, 2016 ). Recently, a European registry for a new prevention trial has been set up ( Vermunt, et al, 2018 ). More information: Chap # 22 and 23.
22
23
See Larson et al, 2013; Bermejo-Pareja et al, 2016 b, and many others.
Recently, several surveys have shown a decrease in dementia incidence. The Framingham Heart Study found this decrease over the last 30 years ( Satizabal et al, 2016 ); the British MRC CFAS in the last two decades
( Matthews et al , 2016 ). In 2017, Derby et al, 2017 found similar data in the Einstein Aging Study.
8

performed simply by controlling the RF and enhancing the PF. Keeping at bay only seven of the RF of treatable sADs (diabetes, obesity, high blood pressure in middle age, tobacco consumption, depression, low education level and physical inactivity) could reduce the number of cases of sAD by a third, or even, for the optimists, by half
24
. Finally, a compelling reason for the pragmatists: delaying the onset of AD by five years would halve its worldwide prevalence
25
.
24
We shall review the main surveys about dementia prevention, from the most provocative ( Barnes & Yaffe,
2011 ) to the most conservative ( Norton et al, 2014) . See FN # 21,237,336.
25
Delaying the onset of AD by only two years will have great repercussions in AD prevalence; delaying AD onset by five years will reduce dementia prevalence by a half ( Brodaty et al, 2011 ).
9

This is a malicious question. In the vast majority of cases of Alzheimer’s disease (AD), the answer is no. However, all diseases have a hereditary component and it is obvious that in some, this component is considerable and others it has hardly any influence. Let us take the case of traumatism: we could look for a genetic cause in the risky behaviour that encourages accidents, but this family-transmitted trait would not be present in many people. Therefore, it seems clear that in many diseases, the genetic component is minimal; whereas the personal component has much more influence (for example, exposing yourself to the cold after strenuous exercise may lead to a cold), or environmental components (exposure to tobacco smoke for many years increases the likelihood of the appearance of several cancers).
Nonetheless, the vast majority of complex chronic diseases (diabetes, arthrosis, arteriosclerosis, myocardial infarction, and AD itself) have a genetic component
26
.
From the genetic point of view, it is 25 years since AD was classified into two types: familial
Alzheimer’s disease (fAD) and sporadic or primary AD (sAD). fAD is, in general, presenile and sAD is senile, about 80% after 75 years. (See figure 2 -4.1). The inheritance of fAD is simple: it is caused by one or more anomalies in specific genes, through dominant Mendelian transmission, which cause alterations in a protein called APP (amyloid precursor protein); the other genes affected are the gene PSEN1 (which generates presenilin 1) and the gene PSEN2
(affecting presenilin 2). These presenilin are enzymes that metabolise APP. The alterations in specific genes give rise to early-onset fAD (normally before the age of 60-65), which represents a very small percentage of all cases (0.5-1%)
27
. The consequence of anomalous genes is an increase in the production of amyloid-beta (
$ ȕ
), or the alteration of its catabolism
(destruction by neuronal metabolism), which in both cases produce an excess of
$ ȕ
, which is deposited in the brain to form neuritic or senile plaques (SP). In normal conditions, the
$ ȕ
(a portion of the protein APP) performs various diverse beneficial functions: prevention from oxidative stress , regulation of cholesterol transportation, and even defence against infectious agents
28
. However, the excess of
$ ȕ
is toxic for the brain. This was the starting point of the amyloid cascade hypothesis, where the excess of
$ ȕ
would lead to toxicity and set off a cascade of pathological events: neurofibrillary degeneration (NFD) or neurofibrillary tangles
(NFT), neuron and synapse loss, and finally dementia. See figures in chapter 6. This hypothesis is accepted in the genesis of fAD but is disputed for sAD
29
.
26
Panoutsopoulou et al, 2013; more data in Chap # 11.
27
Wingo et al, 2012, performed a very important study with the data from 32 Alzheimer's Disease Centres in
USA. They stated that early AD is due to known or unknown monogenetic errors (recessive) and the late AD
(sAD) is a polygenetic disease associated with environmental causes. Van Duijn et al, 1991 a ; and Bekris et al,
2010 quantified the percentage of fAD (it represents less than 10% of the presenile dementias); its gene errors counted 30-70%, PSEN1; 10-15%, APP, less than 5%, PSEN2. (See also: www.genetests.org). Palasí et al, 2015, suggest that 70 years and not 65 years would be the age limit that better differentiates between early and late AD
(sAD).
28
29
See Kumar et al, 2016; they performed an experimental study in this field.
Beta-
DP\ORLG$ ȕ LVDSRO\SHSWLGHSURGXFHGE\WKHFDWDEROLVPRIWKHDP\ORLGSUHFXUVRUSURWHLQ$33,WLV composed of 40-42 amino acids and its deposition in the brain is one of the characteristics of AD. The geneticist,
John Hardy, devised the amyloid cascade hypothesis to explain fAD ( Hardy & Higgins , 1992 ). Moreover, an analogous explanation has been applied to sAD physiopathology. Although amyloid cascade hypothesis has been adapted to new AD advances ( Hardy, 2009; Selkoe & Hardy, 2016 ) it has received many criticisms mainly due to the failure of anti-A ȕ GUXJV WR DPHOLRUDWH $'
Drachman, et al, 2014 ; Herrup, 2015 ), and from systems biology followers ( Kitano, 2002; Wood et al, 2015; Lista et al, 2016).
10

Figure 2. (4.1).
Age distribution of the two types of AD
This figure represents the distribution of the two types of AD: fAD and sAD
In grey background: fAD. Plotted in parallel lines the distribution of sAD. (Schematic image without true quantitative proportion of the two AD types; fAD has, in reality, lower proportion). Dotted lines represent the beginning of sAD burden probably in childhood (Braak & Del Tredici, 2011, 2015) and its incidence decay after the 90 years (?) according Nelson et al, 2011. But, dementia incidence continues to increase in the oldest-old (See FN # 27 & 253).
Figure inspired in Swerdlow, 2008, and modified.
The vast majority of Alzheimer’s cases (around 99%) fall into the category of sAD; also called late-onset AD (few cases appear before the age of 60). Normally (three quarters of cases), sAD appears after the age of 80. Although there are genetic factors, this disease is considered a complex disease , which is not caused by an altered gene, but rather the involvement of many genes (and epigenetic factors) as well as multiple environmental factors
(education, diet, vascular risk factors, physical inactivity, exposure to toxins such as pesticides, among many others). The difficult thing is to identify which factors participate in the disease, as only some are well known, but their importance has not been determined.
The genetic risk of sAD has been quantified as around 30% by some authors, although others raise this figure to 60-80%, which is perhaps a very high percentage in light of some sAD incidence studies on identical twins, which put the figure at 48%
30
. The only genetic trait that has been studied repeatedly and well is the allele E4 of the gene ApoE (ApoE4), as a risk factor (RF) of both types of AD, and specifically sAD (which also has genetic protection factors – ApoE2 and others)
31
. In this context, the environmental component of sAD is
30
The Swedish twin study from the Karolinska Institute (Stockholm) gives this percentage ( Pedersen et al,
2004 ). However, the debate over the genetic sAD percentage is immense (Chap # 11).
31
Bearing the allele ApoE4 is an RF for both fAD and sAD. For sAD it is the only well-established genetic risk
( Yu et al, 2014 ). Probably, this allelic form (E4) would be an ancestral allele from the fascinating history of
11

considered high
32
. Many patients with sAD have some known RF: limited education, obesity, high blood pressure in middle age, inadequate diet and others. The combination of genetic and environmental factors leads to the disease, together with epigenetic factors
33
.
Systems biology considers sAD to be a biochemically distinct entity from fAD (almost another disease)
34
In brief, the vast majority of sAD cases affect very old people and they are the result of a combination of genetic, epigenetic and environmental factors, as occurs in other complex chronic pathologies. For this reason, it should not be considered a genetic disease, as opposed to the infrequent fAD, which is genetic. allelic formation of the ApoE gene ( Corbo & Schachi, 1999 ), which has many biological functions ( Finch &
Sapolki, 1999; Huang, 2010 ). Bearing only one allelic form of ApoE4 increases the AD risk (2-3 times); but having two allelic forms of E4 (one from the father and another from the mother) increase the AD risk greatly
(14.9); fortunately, only 2% of Caucasians have E4/E4 ( Genin et al, 2011) . Possibly, the risk of AD is less in the ancestral populations (African and Sub-Saharan black populations; and in Pygmies it could protect against AD
(Whitehouse 2008; pp: 152 ); see also Chap # 11.
32
33
See Barnes &Jaffe, 2001; Beydoun et al, 2014 .
34
See chap # 11.
Wood et al, 2015; Lista et al, 20016 and Chap # 11.
12

The overwhelming majority of the population believe that it nearly always begins in old age... and you? How would you answer this question?
If you answered “no” – perhaps you know someone who was diagnosed with Alzheimer’s at an early age – you are right: the cases are rare, but they exist. In fact, the first patient described in 1906 by Alois Alzheimer, the German psychiatrist whose eponym has become ubiquitous, was a woman with dementia, Auguste D, who was only 51 years old at the start of her mental decline
35
. When she died some years later, Alzheimer found in her brain some filamentary lesions in the neurons called neurofibrillary threads or neurofibrillary tangles
(NFT), which together with senile plaques (SP) are the two main histological features of this disease.
Let’s leave aside the early onset cases because the question was not about them. If you said
“yes”, your answer was wrong, but don’t lose heart: this is why you are reading this book. In this monograph, the concepts and explanations are repeated, gradually increasing the complexity. What we wanted to ask was when the brain of those who suffer from Alzheimer’s in old age actually starts to become damaged. And, the answer is clear: it does not start in old age, but rather many years (decades) before; sometimes in childhood
36 .
The pathological lesions of AD accumulate little by little in the brain and when they reach a certain level, the patient, who is elderly by then, starts to notice slight memory loss ( figure 3 5.1). At first, we usually do not attach much importance to this – the elderly are often forgetful. After some months or years, the memory loss becomes obvious to everyone although the patient continues to lead a practically normal life. This situation receives the name of mild cognitive impairment (MCI). But often, the disorder proceeds with more memory loss and it begins to affect those activities of daily living (ADL) that require considerable mental capacity: using a mobile phone well, working out the supermarket accounts, managing medication, or navigating unknown streets. At this point, normally the patient, or perhaps his family, goes to the doctor or neurologist, who, so that the family understands, tells them that the absentminded elderly person has the beginnings of Alzheimer’s disease (AD). If a sophisticated imaging technique, a positron emission topography (PET) scan, with specific markers, were performed at this time, it would show the cerebral lesions of AD (beta-amyloid deposits that do not appear in healthy subjects, or if they do appear, do so with less intensity)
37
. Some might ask if the typical AD lesions exist in normal people. This question will not be answered for now – we are not going to delve into another more complex area; it will be covered later.
For now, the important thing is to be clear that the lesions that cause AD-type dementia have
35
The biographer of Alois Alzheimer ( Konrad Maurer, 2005, 2006 ) explained the discovery in his book. Many authors commented on this discovery and its significance ( Amaducci et al, 1986; Boller et al, 1998; Ramirez-
Bermudez et al, 2012) . Amaducci, 1996, disagrees with the disease that Alois Alzheimer described as the founding case of a peculiar presenile dementia; with the available data, it could be a metachromatic leucodisthrophy case, a very rare disease. It is certain that it was not fAD (Consult Chap # 12 for a discussion of this exciting story); the brain has vascular lesions and NFT.
36
Two German pathologists, Braak & Braak, 1991 , have, over many years, evaluated with their team from
Frankfurt University the main pathological findings in AD; they established an evolution classification of AD, which is internationally accepted. The initial NFT biomarkers called “ pretangles” can be found in infants and children ( Braak & del Tredici, 2011 ).
37
See Kramer et al, 2007 and Rosenberg et al, 2015.
13

been in the brain for many years before the symptoms of this disorder appear
38
. Let us banish once and for all the notion that sporadic Alzheimer’s disease (sAD) appears in the brain at the time of memory loss. At this time, the quantity of AD-type lesions in the brain has exceeded the limit for the brain to function.
Figure 3 (5-1).
Alzheimer’s disease evolution (preclinical and clinical periods)
The diagram shows the evolution of the pathologic burden (NFT and SP) in a hypothetical case of AD
(rising line).
At the top of the figure, there is a representation of the AD evolution periods. The long preclinical period can be divided into pre-symptomatic (only histologic) and true preclinical (positive AD biomarkers in CSF, but without clinical manifestations); predementia (MCI) (grey stripe) and with clinical dementia (Mild, Moderate and Severe). The period of years depicted must be considered as standard ranges. Some patients are outside these ranges (outliers): clinical AD cases could die in 3-12 months, but there are cases surviving more than 20 years. Figure inspired by Scinto y Daffner, 2000, and highly modified. Translate into English from the Spanish version of this monograph.
38
The monograph edited by Scinto & Daffner, 2000 and its Chap 1 (pp; 1-29) explain this evolution very precisely.
14

Normally – it has gone past the so-called cognitive reserve
39 of the patient. To use a simple simile, it is like the warning light on a car that shows when the fuel goes below the reserve level. The light on the dashboard comes on and warns us that there is not enough fuel
(cognitive reserve) left to continue the journey happily. Although we could still go a fair distance without the car stopping (dementia), we should fill up to have peace of mind. The aim of medicine is that the individual in this state of cognitive alarm, mild cognitive impairment (MCI)
40
, or pre-dementia, can be treated so as to avoid the emergence of sAD or other dementias.
In brief, AD is stealthy: the lesions (SP and NFT) that cause it accumulate in the brain gradually over decades. Pause to think how this could have been proved – it will be explained later. And, as a picture paints a thousand words, have a look at the diagram that shows the clinical and pathological evolution of sAD ( figure 3 . 5.1) and all will become clearer.
39
The cognitive reserve (CogR) is explained in Chap # 7.
40
MCI ( mild cognitive impairment ) is very popular among neurologists. See Petersen, 1995, 2003, 2011 and
Petersen et al, 2014 ; Bermejo-Pareja et al, 2016 a
15

The figures that define the nervous system (NS) give us an idea of its complexity: 10
11
10
12 neurons communicating with each other with an average of 5,000-10,000 synaptic connections per neuron. The number of synapse operations produced in the brain every second is roughly equivalent to the number of seconds that have elapsed since the formation of the universe, about 10
16
seconds (13.8 billion years). And, in the same way that the universe retains its impenetrable mysteries, we are yet to overcome the challenge to our understanding that the brain represents. This is in no way an easy problem, as we shall see
41
.
Let’s start with the complexity of its structure. Its basic units are the highly specialised cells, the neurons, of which the brain has a huge number; a recent count using modern techniques suggests that there are 8.6 x 10
10
. Two very important features distinguish them from other cells in the human body: firstly, their permanence. In contrast with the widespread view of neurons going into free fall as we get older and more forgetful, once the brain is developed, the neurons that we have stay with us until death (neuron loss in healthy adults and elderly people is minimal). From the end of neurogenesis in infancy, new neurons do not appear
(neurogenesis exists in the adult brain, but is quantitatively minute, except in the hippocampus, striatum and olfactory bulb). The other important feature of neurons is that they emit impulses periodically and that they hold, let us say, mental information both in their cellular structure and in the intricate set of circuits and connections that are recon d and adjust continuously. Another peculiarity of neurons is that they have a kind of “companion cell” that protects them and acts as a support: the glial cells (astrocytes, microglia and oligodendrocytes). The number of these companion cells varies a lot according to the position of the neuron in the NS and the type of animal. In the human cerebral cortex, there is an average of one and a half per neuron. Like a good companion, as well as protecting against noxas, the glia helps support the neuron and acts as a messenger (and as a guide to the neurons when they develop). Another of its functions is to extract oxygen and metabolites from the blood to supply them to the neurons, enhancing neurotransmission . In addition, the oligodendrocytes wrap around the axons of the neurons (with their myelin), efficiently electrically insulating the nerve fibres, which improves neuronal transmission. ( Figure 4 6.1
) shows a neuron, its structure, connections, synapses and its relation with the glial cells).
41
There are many calculations, the clearest, even if we do not know if it is the most accurate, is from Kurzweil,
2012; pp: 562.
16

Figure 4 (6.1).
Scheme of a neuron*
*Neuron structure is schematized (centre). To understand this better, there are four expansions (A1-
A4).
Representations of numbers . 1: neuron body; 2: neuron nuclei; 3: mitochondria; 4: endoplasmatic reticulum; 5: axon; 6: synapsis between two neurons.
Expansions : A-1 ( dendritic spine, 7); A-2 ( axon, 3; mitochondria, 8; neurotubule; neurofilament,
9); A-3, synapsis lengthening with presynaptic vesicle in black and undulating postsynaptic membrane , 10; A-4 (lengthening of the axon and its relation with the glia cells, 5: oligodendrocyte, 1; myelin wrapping of the axon, 12; astrocyte, 12 .
However, the most interesting of the properties of the neurons is the extensive network of synaptic connections that receive information, and then, once it has been processed, transmit it by its axon to other neurons. Moreover, even though neurons are isolated units, a discovery that earned Santiago Ramón y Cajal the Nobel Prize, together they form a network of connections that encompasses our mind and everything this implies: intellect, emotions, motor skills and consciousness. The transfer of information among neurons is tremendous: earlier we said that the average number of synaptic connections for each neuron is around 5,000; in the cerebral cortex, these connections range between 9,000 and 90,000, and reach 175,000 in
17

the Purkinje cells of the cerebellum, and millions in the reticular formation of the brainstem
42
.
Various theories have attempted to give a theoretical framework to this connection machine.
The cognitive revolution of the 50s and 60s tried to explain it as an immense computer. In this formulation, the brain was compared to a structure that analyses information from the surroundings and produces responses (an action-reaction circuit). This theoretical vein continues with the computational theory of the mind, based on the theory that artificial intelligence could emulate, complement or exceed humans in the future
43
, improving on biological cognitive processes and incorporating feelings, meaning that the hypothetical computing process could replace the human brain. The problem is that the human NS does not work like any computer – it cannot be equated to either the hardware or the software . The hard disk or hardware of the computer, composed of silicon circuits (in the future they will be quantum) processes information sequentially and at huge speed (billions of operations per second). In comparison, neurons are very slow processors (the impulse trains range from 0-1 to 200 per second) and the processing is in parallel: various sensory pathways enter the cerebral cortex and, also in parallel, descending motor pathways come from there to the movement and expression organs (extremities and language), forming multiple actionreaction circuits. Figure 5 (6.2) shows this organisation. (It is true that there are computers that process information in parallel, but they are difficult to get – they cost millions of dollars). The software of computers has to be programmed, while the neuronal circuits, even though they have a basis of genetic programming (DNA), are constantly reprogrammed during development and throughout life, according to environmental needs. Dendritic trees, a basic element of brain wiring, are easily modified, like how the branches of trees move according to the direction and intensity of the wind. They establish new synaptic connections and keep or lose the old ones, from the foetal period up until death. Throughout life, the brain displays plastic behaviour that is adapted to the necessities of the surroundings; the synaptic connections are constantly modified in response to the environment (internal and external).
This is why it has been said that “we are our synapses”
44.
42
The number of neurons and their structure are described in all the classic texts such as Nauta & Feirtag, 1977, and the more recent Purves et al, 2011 . The specific works of Susana Herculano-Houzel, 2009, permitted the modification of the cellular counts in the NS. The first counts were done with the optical microscope (two dimensional vision), then by stereological techniques (three dimensional vision) and this author did it with complex techniques (extraction of nervous tissue, which makes it possible in the laboratory to put the cell nuclei in color and to perform an automatized count of neurons and other cells such as glia.
Neurogenesis in mammals during development is a complex process with the creation of neurons from the stem cells and with the apoptosis (neuronal death) of unnecessary neurons ( Reinoso-Suárez, 2004; Ming & Song,
2005). Neurogenesis disappears almost completely in the adult brain except in the hippocampus, striatum and olfactory bulb ( Bergman et al, 2015; Pino et al, 2017 ). Hippocampal neurogenesis could be of importance in AD memory ( Spalding et al, 2013 ) and will be discussed later on in chap #7, FN # 58, and chap # 22 c.
43
The famous gurus of the future tell us these things. See Ray Kurzweil ( 1999, 2012 ) and his website
(www.kurzweilai.net); and the theoretical physicist and futurologist from New York, Michio Kaku ( 2011, 2015 ).
44
LeDoux, 2002, in his monograph, pointed out the importance of the synapses that structure our NS and that change over our life according to our environmental and internal needs and finishes by saying: “ we are our synapses ”.
18

Figure 5 (6.2).
Diagram of the CNS functioning
The diagram shows the action-reaction circuits of the CNS (in parallel). The most primitive is the pain
(sensation)-action (movement) circuit. Several sensations (pain, temperature and others) arrive at the spinal cord and then go to the sensorial cortex (previous thalamic connection). Other sensations do not access the spinal cord. The sensorial cortex communicates with the motor cortex, and the messages of the motor cortex to the muscles are sent by two forms of communication; the extrapyramidal connexions (multi-synaptic, in black ) and pyramidal (quick communication, phylogenetically very recent; grey arrow ). The response of muscles (eyes, limbs) for movements.
The limbic system (emotional drive) establishes several networks for all cortical areas. From the innumerable action-reaction circuits of the NS, consciousness could appear.
*Simplified from NCB, Bermejo-Pareja et al, 2012
Despite the complexity of the human NS, there is something that helps us to study its functioning: its basic structures. Neurons, neurotransmission, glia and synapses are the same in all the NS of every living being. We have inherited the NS of our predecessors, and during evolution, the NS has become more intricate. Nevertheless, the structures of fish, reptiles, birds and mammals, with their ancient origins, are still present in the human brain, even though their appearance and function have been modified. In other words, the organisational diagram of the NS is the same in humans and ancient animals. To make it easier to understand this evolution of the NS, we have a simple explanation, Maclean’s diagram of the triune brain
( figure 6 6.3), which explains how the structures of the NS of primitive animals have been incorporated in the human brain, like the layers of an onion, with the most evolutionarily recent (and external) exerting control over the oldest
45
.
45
Butler, 2009 in the Encyclopaedia of Neuroscience, Squire, ed, 2009, and a previous text ( Squire et al, ed,
2008) comment that the triune brain has very old roots ( Smith CU, 2010 ). Paul MacLean 1990, concretised it, in the last part of the 20th century, and found some acceptance but more criticism (see Butler 2009 , and Pinker,
1997; pp: 476-78 for an accessible explanation); in summary, the CNS had three parts phylogenetically, which joined like onion layers, and whose functioning is integrated. In mammals and humans, the cortex broadens at the top (nearly 80% of the human NS). Several monographs analyse this evolution ( Sarnat & Nesky, 1974 ;
19

Figure 6 (6.3).
The ´triune´ brain (Cerebral structure according to evolution)
The top image represents the scheme that describes the human brain in onion layers (according to
MacLean). The bottom image depicts the CNS of a standard mammal with the phylogenetic origin of its structures. The human cerebral cortex has increased so much that it forms 80% of the total CNS
(not in the standard brain depicted). The ancient brain origin of the reptilian brain is in black; the paleo-mammal brain is represented in grey (light); and the neo-mammal in dark grey. (See the text).
*Taken and modified from NCB , Bermejo-Pareja et al, 2012
Mesulam, 1985 ; and recently, Damasio, 2010 ). Innumerable texts explained how the human brain functions, from the first hierarchical view of H. Jackson ( Lassek, 1970 ), including the Nobel Laureate, Ramón y Cajal,
1904 . Historically noteworthy are: Penfield & Rasmussen, 1950 , with their data on cerebral stimulation. In the last two decades and for their accessible content we mention Markus, 2008; Linden, 2010 and Rose, 2008 . The
Rita Levi Montalcini, 2000 text is a very interesting and poetic. Probably the monographs of Damasio ( 1999,
2010 ) are the best for the non-professional reader. It is clear that all the explanations are in some way speculative because we do not know yet how the brain functions. Important international projects are trying to overcome our ignorance: the Blue Brain Project will analyse the functioning of the rat’s single cortical column. The large
BRAIN Project (http://www.braininitiative.nih.gov/), coordinated by the Spanish neurobiologist Rafael Yuste, and its associated Human Brain Project from European investigators ( HBP, https://www.humanbrainproject.eu/es) have enormous budgets. The Human Connectome Project has investigated, with the aid of fMRI, the main connections of the cortical areas ( Glasser et al, 2016) . The most unknown area of brain functioning is consciousness. For this unique brain function there are explanations from physics (the Nobel Laureate physicist Schrödinger (Spanish edition of 2016 ); Roger Penrose, 20007, which indicate that consciousness is a quantum process that does not depend on the classical functioning of neurons
(perhaps it is located in the neurotubules -surprising!-, and Kaku, 2014 ). Classical neuroscientific explanations are from Eccles, 1989, Damasio, 2010, Baars & Gage, 2007, Laureys & Tononi, 2009 (from a clinical standpoint). In our opinion, the Fuster, 2009, 2014 explanation is the most comprehensible.
20

In an accessible and schematic way, we can extend the triune brain simile to show the evolution and structure of the central nervous system (CNS). The oldest and medial layer: the brainstem and rudiments of other more complex structures represent the “reptile” brain. The reptiles with this kind of brain perform automated movements and basic vital functions
(feeding and reproduction); the second layer represents the so-called “limbic brain” (from the little-developed mammal or proto-mammal), which is present in birds and basic mammals. It performs more complex motor and behavioural functions (instincts and certain social behaviour). In order to do this it requires an organ that integrates sensory information and movement: The thalamus and another that regulate the vegetative and hormonal functions: the hypothalamus. It also has the amygdala, a structure that mediates emotional reactions (fear, danger and flight). In addition, finally, it contains a rudimentary cerebral cortex (archicortex): the hippocampus (meaning seahorse because of its shape), which performs memory and coordination functions. In the brain of superior mammals (primates and humans), the cortex or cerebral cortex is highly developed (in man this represents 80% of the CNS), with a highly developed frontal lobe (and prefrontal cortex), which is the most hierarchical structure in the
CNS. The human cortex is a fine lamina, 0.5cm thick, with several neuronal layers and is the main site of higher cognitive functions: symbolic capacities (oral and written language), executive control and self-awareness, through reverberating neuronal circuits that are still poorly understood ( figure 7 -6.4) show the divisions – lobes – of the cortex) and its functional subdivisions ( figure 8 -6.5).
21

Figure 7 (6.4).
Brain representation in lateral and sagittal vision
Top image: Lateral vision. 1: lobule frontal; 2: lobule parietal, 3: lobule occipital; 4: lobule temporal
Bottom image : Sagittal image. 5: cerebellum; 6: Fourth ventricle; 7 Pons; 8: Cerebral stem; 9:
Cingular cortex; 10 Corpus callosum
Modified from BCN, Bermejo-Pareja et al, 2012
22

Figure 8 (6.5).
Main functional subdivisions of the cerebral cortex
Cerebral cortex detail showing several functional subdivisions of its lobules: Frontal Lobules (F.L.) subdivided into prefrontal area, frontal association area (FAD) and frontal motor zone (F.M);
Parietal lobe (P.L.) that includes the sensorial zone (S.P) and the association parieto-temporooccipital (P-T-O); the occipital lobe (O. L) with its visual cortex). The functional subdivisions of the lobules are very numerous (180 have been described with fMRI; Glasser, 2016), for that reason these subdivision diagrams must be considered as schematic
Although the cortex controls the functioning of the NS, mainly consciously, the most ancient brain layers perform their functions in an integrated fashion, relatively independently of the cortex and, largely, automatically (i.e. unconsciously). An example: the control that the brainstem (reptilian brain) exerts on breathing is unconscious but we can consciously breathe in whenever we like, when the frontal cortex demands. Similarly, many feelings: anger, fear and love stem from the limbic system, but we can control them or, sometimes, rationalise them.
How can we integrate these facts with AD? Well, the first brain structures affected by AD lesions are the ancient regions of the brainstem, followed swiftly by the hippocampus (the old archicortex), with its association and memory functions; it associates recent information (from the senses with their affective component) with cortical areas that store old memories
46
. The appearance of recent information in the consciousness requires the integrity of the hippocampus in order to recall memories and incorporate new data ( figures 9 6.6- and 10 -
6.7). To put it another way, the disruption to the hippocampus and adjacent entorhinal cortex affects memory, first recent memories and then old memories. This is why AD usually shows itself initially in the loss of recent memories. As AD progresses, the cortical association areas
46
Braak y Braak, 1991, performed the most precise studies, at initio . Then, H Braak and co-workers continued the studies over decades (included Jucker & Walker, 2011 ).
23

are affected (the temporal and frontal lobe and a large temporo-parietal area; figure 8 -6.5).
At the end of AD, the whole brain is damaged
47
.
Figure 9 (6.6).
Hippocampus representations over the cortex surface
Hippocampus representation (girus dentatus) and connected regions: entorhinal cortex (that connects with the hippocampus), and it is the zone in which the first lesions appear in Alzheimer’s disease) and the amygdala. It is necessary to uncover the temporal lobe to be able to see these structures (that are deep down). See figures 6, and 7.
47
Rapoport (1989, 1990) has emphasized the biological significance of AD cortical alterations, over time.
Rapoport thought that AD is a progressive illness that affects the phylogenetically more recent cortical areas.
Also, see Ohm et al, 1995 , and Schönheit et al, 2004.
24

Figure 10 (6.7).
Hippocampus representations over the cortex surface
The scheme represents a transversal cortical section (only one side). This figure complements figure 8.
In humans, the archicortex (hippocampus) and paleocortex (entorhinal cortex) are very small in comparison to neocortex (temporal and parietal lobules schematized).
The typical pathology of Alzheimer’s is shown with its two principal lesions (SP and NFT) in figures 11 (6.8) and 12 (6.9), and its deposits in the brain ( Figure 13 6.10); table 2 (6.1) describes other lesions observed in AD
48
. The promise was kept: here we have the anatomy and functioning of the NS, which is difficult, yes, but only the essential parts necessary to understand why Alzheimer’s first affects recent memory, and then, other memories, and finally the whole NS.
48
In all neuroanatomical and pathological texts, it is possible to find the description of AD pathology and specifically in Terry et al, 1999 . Teresa Gómez-Isla, a Spanish neuroscientist, working at Harvard, described in detail the initial lesions in AD in the entorhinal cortex and hippocampus ( Gómez-Isla et al, 1996, 1999); other less frequent lesions are shown in table 2 ( Terry et al, 1999; Hyman et al, 2012 ).
Briefly, we comment that there is disagreement in the diagnostic pathological features of AD. The most accepted diagnosis requires three lesions: SP, NFT and NP, with a quantitative and qualitative distribution
( Hyman et al, 2012 ). This statement came from a broad consensus (NIA-AAD) and works quite well ( Montine et al, 2016 ). A more detailed analysis of this subject is outside the scope of this monograph.
Figure 13 (6.10) describes the evolution of AD lesions over time (SP and NFT).
25

Figure 11 (6.8).
6HQLOHSODTXHDQGQHXULWLFSODTXHZLWK$ ȕ EUDLQGHSRVLWLRQ
0LFURVFRSLFRSWLFLPDJHOHIWGHSLFWLQJDFHQWUDOEODFNDFFXPXODWLRQ$ ȕ WKDWIRUPDVHQLOHSODTXH
(SP), and when neurites surround this SP, it is a neuritic plaque (NP). Electronic microscope (right)
VKRZVWKLV$ ȕ GHSRVLWLRQPDUNHG
Photography kindly donated by the Dpt. of Neuropathology (HU 12O) and taken from NCB, Bermejo-
Pareja et al, 2012.
Figure 12 (6.9).
Neurofibrillary threads in neurons (neurofibrillary tangles, NFT)*
(tau protein brain deposition)
A)
A) Microscopic images of neurofibrillary threads .
Microscopic optic image that depicts neurons with a lot of black stain (NFT) on the left. Electronic microscope (right) showing neurotubule (neuron skeleton) with alterations (twisting) and constrictions marked with arrows. Courtesy the Dpt. of Neuropathology (HU 12O) and taken from NCB, Bermejo-
Pareja et al, 2012
26

B) Neurofibrillary tangle formation
B) Neurofibrillary tangle (NFT) or NFD .
Tau protein sustains the neurotubules like a trellis. (In the scheme it appears as black rectangles). Tau phosphorylation by enzymes loses its support function that determines the disorganization of neurotubules producing the NFT or NFD. Modified from Terry et al 1999; pp: 363.
A
Figure 13 (6.10).
Abnormal protein (
$ ȕ DQGWDXGHSRVLWLRQLQWKHEUDLQDQGLWV pathologic evolution over time
A) NFD (or NFT) deposition in the brain. The NFD deposition begins in the brain stem nuclei (locus ceruleus) as “pretangles” (left), continues to the hippocampus (continuous arrow) and to the cortex
(dashed arrows); from the hippocampus it goes to the prefrontal cortex (centre) and then goes around all the cortex regions (left). Imitated from Jucker & Walker, 2011, but complemented with Braak et al,
201, 2015 information
27

B
B) Senile plaque (SP) brain deposition. The A ȕ
and SP deposition begins in the cortex (left) and spreads later to the limbic system and hippocampus (centre) and caudally to the brain stem and cerebellum (right). Imitated from Jucker & Walker, 2011 and complemented with data from Thal et al,
2002
Table 2 (6.1). Main cerebral lesions associated with Alzheimer’s disease &
Macroscopic appearance
Mild decrease of cerebral weight
Atrophy of the cortical gyri (more clearly in frontal, temporal and parietal lobes)
Microscopic lesions
Senile plaques* (SP)
ZLWKFHQWUDO$ ȕ GHSRVLWLRQ
Figure 10 )
Neurofibrillary tangles (NFT) **
(Abnormal tau protein in the neuron filaments) ( Figure 11 )
Neuronal loss
Decrease and alterations in synapses
Other less common characteristics
Granulovacuolar degeneration (in the pyramidal neuron soma)
Hirano bodies (in hippocampus neurons)
Amyloid angiopathy (small vessel disease)
Abnormal protein accumulation (TDP-43) and others, and gliosis
& Summarized from Terry et al, 1999 and Hyman et al, 2012
*SP have several types, one of them is the neuritic plaques (NP), when dystrophic neurites appeared in the SP.
** NFT could be present in neurons, neuropil, and dystrophic neurites; these three forms of NFT, some authors call neurofibrillary degeneration (NFD), Iqbal et al, 2009.
28

In an article that went somewhat under the radar in its time, an eminent Alzheimer’s researcher, Robert Katzman and his team
49
put together ten cases of women in whose brains they found a large quantity of lesions typical of Alzheimer’s (senile plaques and neurofibrillary threads), but which had not led to any cognitive disruption. These researchers explained this by appealing to size: as the women in question had larger than average brains
(in volume and weight), the accumulation of lesions characteristic of Alzheimer’s disease
(AD) did not have the same effect on them as in other people with a similar quantity of lesions and normal or small brains. The concept of cerebral reserve had been born. The subject remained buried in the mass of medical literature, although it had an impact among researchers. The concept of cerebral reserve was applied to a presumed static, structural capital that allowed the brain to function adequately and resist brain lesions, despite the faults caused in its biological machinery.
The concept of cognitive reserve (CogR) was formulated at the beginning of the 90s with various types of AD studies. Cerebral blood flow studies showed that patients with AD and a high level of education coped better with larger deficits in cerebral blood flow in some areas of the brain than those who had higher flow; in these cases education would have the effect of a reserve against AD; the same happened with those who suffered brain traumas
50
. Later, in population-based studies it became apparent that the risk of dementia was greater in people with limited education than in graduates
51
. The same was true of people who had worked in a job that required only a basic level of training compared to those who had worked in more intellectually demanding professions. And, that was the how the concept of cognitive reserve came about, more biologically flexible and functional than mere brain size
52
.
There would be two type of cerebral reserve: one passive in nature called “ brain reserve” , whose main proxy would be the total intracranial volume (it is based on the number of neurons)
53
. CogR appeals to the concept of the active “capital” that is brought by the multiple
49
Katzman et al, 1988. It is worth mentioning that Robert Katzman and Robert Terry, from the Dpt. of
Neuroscience of the California University in La Jolla (a beautiful city as its Spanish name indicates) were the pioneers in the modern study of AD pathology. Their AD monograph had several editions and it is a book of reference in the field. Terry indicated that the synaptic loss in AD correlates more with cognitive impairment
WKDQWKH$ ȕ RU1)7EXUGHQ
Terry et al, 1994, 1999, 2000 ). Katzman was the leader of the Conference that in
1978 ( Workshop Conference on Alzheimer's Dementia and Related Disorders ) joined presenile and senile AD into one entity: AD-type dementia ( Katzman et al, 1978 ).
50
Sazt, 1993, described the brain reserve threshold in head trauma. Later on, CogR was analysed in stroke
( Mirza et al, 2016 ), PD ( Hindle et al, 2014 ), and several dementias.
51
Historically, the first large population-based survey was performed in China ( Zhang et al, 1990 ), in which
Katzman was co-author and leader. This put on the table the importance of education in dementia prevalence
(more frequent in females, who were mainly illiterate). Education behaves as a “reserve” that decreased the bad consequences of the lesion burden in dementia and AD ( Katzman et al, 1988, 1993; Stern, 2002 ). The
EURODEM survey confirmed these data ( Hofman et al, 1991 ; Letenneur et al, 2000 ) and many other surveys, including our Spanish survey NEDICES in which being illiterate had near fivefold higher risk for AD compared to having secondary or higher studies ( Bermejo-Pareja et al, 2008b; Contador et al, 2015 a ).
52
Staff et al, 2004 analysed the CogR components in the Scottish Aberdeen long cohort, summarizing that education and occupation throughout life were more important for the CogR than static total intracranial volume
(brain reserve). (See FN # 224, 287). Recently, the large Whitehall II study confirms low-level occupation to be a proxy of CogR ( Rusmaully et al, 2017 ), and a systematic review (Chapko et al, 2017) confirms both data.
53
The recent study of Groot et al, 2018 has demonstrated that both brain reserve and cognitive reserve contribute to delay dementia onset.
29

connections of neuronal and synaptic networks produced in the brain, which is trained through mental and physical activity, against the appearance of brain lesions. Cerebral reserve
(the number of neurons in the brain) can be comparable in many people, be they illiterate or orchestra conductors. In contrast, activities such as reading and writing from childhood (better if done in more than one language), studying to work in a profession and continuing with this training throughout life would increase the CogR, rewarding these “intellectuals” in comparison with those who do not make this effort. This cognitive exercise continues to increase the mental and functional capital, based on multiple neuronal information networks, which are reinforced over the years and form the scaffolding of memory and intellect
54
. The concept of CogR has been tested in experimental models (rodents and dogs) subjected to cognitively enriching environments. It is, therefore, a biologically corroborated fact
55
.
The data collected over the course of many studies indicate that intellectual activity is established in the first years of infancy, when most of the brain is formed and when the neurons make their most important connections. It can continue to be strengthened with a lifestyle that increases the need for greater neuronal assembly (language learning and further education) and also with a healthy lifestyle (physical exercise and participation in social activities). All of this leads to a defence against brain lesions. In this way, with the help of
CogR, we can increase the biological resistance to the appearance and development of the symptoms of dementia and AD. The diagram in figure 14 A (7.1) graphically explains the relationship between CogR and the appearance of AD in three people with differing levels of
CogR. Figure 14 B (7.1) complements diagram 14 (A) to better explain, how CogR works, that when the cerebral pathological burden of sAD exceeds it, the patient starts to suffer cognitive deficits.
54
Many investigators had explained the CogR concept. Yaakov Stern, Columbia University in New York, has been one of the leaders in this area (Stern, 2002, 2005, 2013 ) analysing its clinical manifestation and pathology; also, he collaborated in the NEDICES data analysis ( Contador et al, 2017 ). Richards & Deary, 2005, stress the
CogR dynamic construction throughout life . Mortimer et al, 2005 discuss the markers (clinical, biological, neuroimaging) of CogR. In addition, several pathological studies maintain the importance of education as a proxy of CogR ( Katzman, 1988, Roe et al 2007; Brayne et al, 2010. In a systematic review and meta-analysis, covering many studies, Meng & D’Arcy, 2012 , concluded that CogR is a theoretical construct; moreover, it is a robust construct over the population studies performed.
55
Many authors, through experimental animal studies, have validated the concept of CogR ( Milgram et al, 2006 ;
Cracchiolo et al, 2007 ; Borroni et al, 2012); summary in: Xu et al, 2015 b
30

A)
Figure 14 (7.1).
Scheme to explain the cognitive reserve (CogR)
Evolution of pathologic burden in dementia and CogR . In a case of AD, the pathologic burden could increase throughout life (bold black) and according to CogR (grey arrow). The clinical appearance could be: A) standard CogR, AD onset about 80- 85 years; B) Individuals with low CogR, onset prior to 75 years; C) High CogR: No AD onset or onset very late, about more than 95 years.
B)
B) AD pathologic burden, CogR and clinical manifestations . The AD pathologic burden increase throughout life (ascendant arrow), mainly during aging in an AD case. When the CogR is lower than the pathologic burden the clinical manifestations begin: cognitive impairment (MCI) and dementia.
See figure 3 (5.1) .
“How could this idea of CogR be translated into a biological entity in the brain?” This is where the problem lies. It is not easy to translate a theoretical construct to biological parameters, above all if a unanimous definition is lacking. And, more so if CogR does not
31

mean a reduction in the pathological burden in dementia, but rather that it simply makes the appearance of dementia and AD more unlikely
56
.
Nevertheless, neuroimaging studies have been carried out, where the functioning of the brain is observed with functional magnetic resonance imaging (MRI) and positron emission topography (PET). These studies confirm that brain size and the number of neurons and of synapses and dendritic trees at cell level (cerebral reserve) protect against possible brain lesions. There are theories that explain CogR in AD as a mechanism that activates new brain circuits that are not usually used, unless lesions appear in the hippocampus, and there are other findings
57
. Be that as it may, the greater the CogR, the greater the brain’s capacity to withstand the pathological burden in any of the many afflictions that affect the brain: severe cranial trauma, multiple sclerosis, stroke, neurodegenerative disease (NDD) such as PD, and above all AD-type lesions (thus CogR is not only applicable to AD, although this is the most typical and best studied example
58
).
“Do these theories mean that, as we have heard so many times, people use no more than a tiny percentage of the brain?” The answer is no. There is no proof, despite how deep-rooted this opinion that we only use part of the brain is. On the contrary, functional neuroimaging has confirmed that we all use the whole brain, even when we are at rest; what happens is that those with greater CogR have the advantage of more complex neuronal circuits. Their brains are better constructed and trained, and more expanded functionally.
“Is cognitive reserve increased because when we study a lot we form new neurons?” Well, no.
The neurons are the only cells in the body that, once developed in the brain (in infancy and youth), remain throughout life. Neurogenesis (the formation of new neurons) occurs while the brain is being formed, but not in adults – although possible, it is seen as quantitatively unimportant, except in some specific areas: the hippocampus and others (see chapter 6).
Neurogenesis is an area of intense research, due to its possible therapeutic implications. It is sure that in certain mammals, considerable neurogenesis exists in the adult brain but the same is not true for humans and only the future will show if, in our brains, the new neurons that appear in the hippocampus and other areas perform an important role in memory, or CogR, as occurs in other mammals
58
.
56
Multiple data indicate that CogR does not affect the pathological burden in AD ( Roe et al, 2007; EClipSE study -Brayne et al, 2010 ), it only determines the delay in the appearance of cognitive impairment and dementia
( Contador et al, 2017; Soldan et al, 2017 ). Moreover, some studies indicate that education is associated with cerebral vascular lesions in dementia ( Del Ser et al, 1999 ).
57
In reality, it is difficult to unravel the biological bases of CogR. Spanish investigators have analysed new possible circuits, in several individuals with high CogR, when the AD lesion could affect the hippocampus
( Ávila et al, 2015 ). In this context, an increase of presynaptic protein in individuals with high CR was described
( Honer et al, 2012 ). In addition, van Loenhoud et al, 2017 maintains that an index of grey matter would be a
CogR proxy. These studies are interesting but, really, we do not know precisely the biological basis of CogR, nor do we have a unanimous CogR definition ( Harrison et al, 2015). See more explanations in FN # 280 .
58
Adult neurogenesis is common in mice (wild or knock out with human AD genes). The new neurons appear in several brain regions. In the hippocampus, neurogenesis correlates positively with mouse memory. In humans, after intense investigation in this field, its existence is proven ( Spalding et al, 2013; Bergmann et al, 2015 ) (See footnote # 37). The discovery of hippocampus neurogenesis is a matter of fiction-science. The brain incorporation (also in the hippocampus) of radioactive Carbon (C
14
) due to atomic bombs during the Cold War and its human alimentary incorporation (plant photosynthesis integrates the environmental C
14
), permitted us to date the birth of new neurons ( Spalding et al, 2013 ). The quantity of human hippocampus neurogenesis has not determined with agreement between investigators; in transgenic AD mice it is great ( Gu et al, 2014); although
32

But, “how is cognitive reserve measured and how do I know if mine is high or low?” I´m not looking for trouble – the measurement of CR is complex. It could be measured in various ways: the quantification of intelligence before the onset of AD (pre-morbid intelligence), education throughout life, working life, even with socioeconomic variables and lifestyle
(social integration, absence of addictions, etc.) among other variables. These parameters could be measured in each person to come up with a general idea of his CogR. So much so that some studies have established an index composed of these and other factors. Some authors, however, have taken a more direct approach and prefer to measure the intelligence quotient
(IQ), i.e. a measure of intelligence, with a test (WAIS, although there are others), and others use a more simple method: years of education, or educational qualifications achieved. In
NEDICES, verbal intelligence measured with a test is a better indicator than years of education
59
.
To sum up, it can be said that cognitive reserve is a mechanism that “compensates” the damaging effects both of acute (trauma, stroke) and chronic lesions (AD, degenerative diseases) in the human brain, without a cognitive deficit appearing. It is a reserve that is forged in infancy, but which can be increased throughout life, even after the onset of AD, through cognitive rehabilitation
60
.
too much neurogenesis may jeopardize memory retention , Mo ngiat & Schinder, 2014 . In humans, some authors thought that the neurogenic loss in AD could be a cause of AD memory deficits in AD ( Mu & Gage, 2011 ), and for some of them this is certain ( Hollands et al, 2016) and they plan new therapies. An exciting subject; we need more studies.
59
The measurement of CogR has been disputed ( Valenzuela & Sachdev, 2006 a, b; 2012 ; Bennett el al, 2014;
Arenaza-Urquijo et al, 2013, 2015).
These authors reviewed this subject and the importance of lifestyle in its construction. Del Ser et al, 1997, and Contador et al, 2015 a , discuss the importance of verbal intelligence in its definition with data from the NEDICES cohort.
60
Valenzuela & Sachdev, 2006 a, b, performed two reviews and maintain that CogR would be initiated very early in life (language acquisition is important ( Antoniou & Wright, 2017 ). Liberati et al, 2012, indicate that
CogR could increase in AD patients treated with cognitive therapy.
33

The information has come from various sources and this is why it has the consistency required for scientific certainty. We shall start with the population-based studies.
The biomedical population-based studies that evaluate the evolution of a cohort of people over time are very useful for determining how diseases appear, and their causes (see next chapter). These studies keep track of and evaluate a set of people, generally selected randomly from a large population: the inhabitants of a small town; workers in a factory; nuns in a convent; or people who volunteer. The mental state or presence of a disease in these participants is analysed with a questionnaire (sometimes with medical examinations). The studies that provide the most data – and the most difficult to perform – are those that examine the participants periodically to check how their health is evolving or the specific aspects of health that are being studied. Sometimes they also study mortality. In this way, for a certain disease, they can determine how many people suffer from it (prevalence), when it appears (incidence) and detect risk factors (RF) and prevention factors (PF). These data can even be extrapolated to a larger population (province or nation). These studies usually have concrete aims and there are numerous examples in the world
61
.
One population-based study that has contributed information relevant to Alzheimer’s disease
(AD) is the Framingham study
62
. It gets its name from the small city near Boston where it was performed. In this cohort, started in the 40s, the researchers were looking for the RF of heart diseases and the study became famous when it was found that obesity, diabetes, and high blood pressure were RF for myocardial infarction (among other cardiovascular diseases -
CVD). These days this seems an obvious relationship but it was the findings of the
Framingham study that laid the foundations for a preventive culture for CVD, based on the control of RF, which has transcended the purely medical world and is known by everyone. It was also in this cohort study that, from 1975, they performed psychometric tests on the participants every two years, to evaluate memory, attention, reasoning ability and other cognitive skills. 13 years later the researchers concluded that many of the people who developed dementia in old age experienced, gradually and before it appeared, a decrease in their memory, above all verbal memory, which they themselves did not notice. On performing a similar examination after 22 years of follow-up, they observed that in a group of participants the decrease in memory continued (above all in learning words, retention and recall) and in the capacity for abstract reasoning. If this decline continued for 10 years or more, this was the best predictor for dementia (or AD). It is important to point out that these cognitive decreases
61
The neurological team of the University Hospital “12 de Octubre” (UH12O) established, with many collaborators, an elderly cohort (5,278 participants) to investigate the main elderly neurological disorders: CVD and stroke, PD, tremor, MCI dementia and AD with mortality data ( Bermejo et al, 2001; Bermejo, 2007 ;
Morales et al, 2004 ), see chap # 22e.
62
The insurance companies were the first that detected the relationship between obesity and mortality at the beginning of the 20 th
century; but the biomedical merit is from the Framingham cohort. This survey defines the
CVRF for obesity and DM2. This survey began in 1948 with 5,209 Framingham city residents (1/3 were volunteers) (see FN # 230, 276, and 308). Every two years all of the participants had a medical examination. In
1971 the children of the first cohort initiated another cohort (5,214), examined every four years . Linn et al, 1995, and Elias et al, 2000, described the findings in relationship with dementia and AD. In 2001, another cohort was initiated with the grandchildren of the first cohort, mainly to investigate CVD genetics ( Tsao & Vasan, 2015 ).
34

were subclinical, i.e. very subtle, so neither the participants nor their families usually spotted them, but they did show up in psychometric tests.
Many other studies of the same nature have confirmed these observations in the United States and Europe, which shows that in many cases of AD there is a long preclinical period of discrete cognitive decline (above all memory) before dementia appears. One of these has the concise name “nuns” as it was carried out on a Catholic Congregation of Sisters of Nôtre-
Dame. The research team managed to get the Sisters to give them the diaries that they wrote at the age of 22 (when they entered the Congregation). Using these texts, they established the level of linguistic knowledge that these women started with, as well as their intellectual capacity (density of ideas and grammatical complexity). In addition, at the start of the study they performed tests and medical examinations. And, finally, the nuns agreed to donate their brains to complete the investigation with post-mortem pathological information. The study was mainly carried out in the convents of this order in Milwaukee (Wisconsin). The results of the follow-up and the brain analyses showed that the nuns with lower intellectual level in their writings in their 20s had a greater risk of dementia and AD, and also that the vascular lesions in the brain encouraged the appearance of this disease
63
. In addition, to round off these examples of population-based studies that have investigated the beginnings of AD, I am going to mention a European study: PAQUID, a French cohort that has been followed for 20 years.
This investigation showed that in subjects with a high educational level, the cognitive decline usually starts about 15-16 years before the appearance of dementia, while in those with very limited education, the dementia appears roughly seven years after the cognitive decline
64
.
Besides the population-based studies, there is more research that reveals that the manifestations of cognitive decline can appear decades before the appearance of dementia: the pathological data from the brain. A long time elapses between the first brain lesions typical of
Alzheimer’s and the appearance of dementia. This time lapse can be seen with more precision and more definitively under the microscope than with psychometric tests. In the 90s, the anatomy professors Braak and Braak
65
established six stages of AD, based on the distribution of neurofibrillary threads (or neurofibrillary degeneration (NFD)) that accumulate in the brain of an Alzheimer’s patient. Stages I and II correspond to the initial phases of AD and are associated with neuronal alterations (the presence of NFT) in the entorhinal region (adjacent to the hippocampus, figures 9 (6.6) and 10 (6.7) in the temporal lobes. These initial stages are not accompanied by cognitive impairments. However, from the affected entorhinal region, the lesions spread through the limbic system (through the hippocampus and temporal lobe, figure
13 (6.10) and the patient starts to have memory deficits. The brain lesions do not reach the cerebral cortex until the most advanced stages (V and VI), when the cortical areas of
63
The Nun Study prospectively investigated 678 Nôtre Dame Catholic nuns (75 to 102 years) in the cohort baseline in 1972. The nuns donated their brains, so all the participants had a necropsy. Snowdon, 1997, 2003 , and Mortimer et al, 2003, 2012 , among others, described the interesting findings of this innovative study.
64
The PAQUID survey is a prospective cohort, composed of a population-based representative sample. In
December 1987, people aged 64 and above, inhabitants of Gironde and Dordogne, two administrative regions of
France, formed the cohort ( Amieva et al, 2014 ). See Chap # 22e.
65
Heiko Braak and Eva Braak (died in 2000 at the age of 61) were Anatomy professors in Frankfurt (University
J. W. Goethe). They performed the pathologic study of AD and PD with their brain bank ( Braak & Del Tredici,
1991, 20111 a ,b, 2013, 2015) , which has been continued by their collaborators ( Ohm et al, 1995; Thal et al, st
2002) . Heiko Braak was senior investigator in his University, but in the 21 century works in Ulm University
(Germany).
35

association (fronto-temporo-parietal) are fundamentally compromised. The period between the first stages and the last is very long. According to Braak and Braak, it could take about 16 years to go from Stage I to II; around 14 from II to III, when the first manifestations of cognitive deterioration appear; 13 years from Stage III to IV; and five more from IV to V, when AD clearly shows its face. This pace can accelerate after the age of 65. With these classifications, it is clear that the NFD lesions can begin in early adulthood, (and even in childhood if we consider the pre-NFD lesions). Although opinion is divided in the published studies, the data indicate that sAD starts with NFD, which is later usually accompanied by senile plaques (SP). We also know that the cortical association areas are preferentially affected, although the whole brain will be metabolically damaged when AD reaches its final stages
66
. In summary, the pathological findings indicate that the lesions characteristic of AD is produced slowly over decades. Thus the pathological findings corroborate the clinical observations of subtle memory deterioration decades before the appearance of sAD.
Modern neuroimaging techniques (SPECT, MRI and PET) also confirm these brain alterations in Alzheimer’s patients. PET, in particular, with the administration of specific contrast materials, allows the evaluation of deposits of amyloid-beta (
$ ȕ LQWKHEUDLQ 67
. This accumulation appears in people who are cognitively normal, but always to a lesser extent than in subjects with cognitive deterioration, and of course patients with AD who generally have
WKHJUHDWHVWDPRXQWRI$ ȕ LQWKHEUDLQ$VWK ese techniques that allow us to “look at” healthy and ill people’s brains are recent, their findings do not yet have the consistency of the clinical and pathological data with long follow-up. However, neuroimaging confirms the slow evolution of sAD revealed by the studies cited, and the cases of familial Alzheimer’s (fAD) have been confirmed with spinal fluid and neuroimaging studies
68
.
This monograph will attempt to explain how it is likely that before the appearance of lesions that can be detected with psychometric tests, microscope or PET scans, the warning signs for
AD, metabolic “fingerprints” that make this disease more likely can appear in the brain. In short, the degenerative process characteristic of sAD is established in the brain over the course of decades (it begins pathologically after one’s 20s in many cases) and shows itself in old age. Figure 2 (4.1) shows graphically what has been explained about the evolution of pathological lesions and clinical manifestations.
66
Rapoport, 1989, 1990, indicated the great possibility that advanced AD affected the cortical association areas and posterior hippocampus (See FN # 47). He considered that the neurons of these areas would be affected because their neurons were phylogenetically recent due to human genetic evolutionary mechanisms. AD begins early (NFT) in the entorhinal cortex and hippocampus, and also in the stem nuclei ( locus ceruleus ) in the form of
“ pretangles” o pre-NFT (Braak & del Tredici, 2011 a ). According to Arendt et al, 2015 the NFT could appear in several locations at the same time. The fact is that early hippocampal lesions determined the early amnesic deficit in AD.
67
Summarised data from the evolved neuroimaging in AD; this can be found in Bradley KM et al, 2002; Caselli
& Reiman, 2013 ; and Jansen WJ et al, 2015 . Johnson KA et al, 2016, indicates that the AD PET-tau can clarify the subject. Schmitz et al, 2016, by means of fMRI, suggest AD beginning in the brain stem.
68
Prospective studies in fAD showed CSF and neuroimaging alterations two decades before the clinical manifestations ( Bateman et al, 2012 ). The Colombian retrospective cohort, 493 participants, who have PS1
E280A gene, which is the original mutation of the Basque conquerors of the 15 th
century; follow-up over 20 years has demonstrated preclinical cognitive decline (word remembering) 12 years previous to MCI appearance
(and 8 years in advance had biological alterations -CSF and PET). High education delayed fAD onset ( Aguirre-
Acevedo et al, 2016 ).
36

The three next chapters are very technical and the following one is historical. Readers without biological knowledge or interest in the subject can skip them without harming their understanding of the monograph. However, they will miss the chance to learn something new and, who knows, to gain a little protection against possible cognitive decline in old age.
37

In the previous chapter, examples of population-based studies were described, showing their efficacy in research into the evolution of AD. Now is a good time to examine how medicine expands knowledge about health and many diseases using this tool (mainly of research)
69
. It is an integral part of medical work not only to care for the sick patient but also to be curious and investigate where, how and why diseases develop, how they can be cured and the real effect of the treatments we deliver. All this can be investigated using various types of studies.
The majority are clinical, i.e. performed on patients who see doctors (primary, specialised or hospital care). However, population-based studies are not carried out on patients, but rather on the general public (healthy and sick). This is the most characteristic area of operation for epidemiology
70
.
“Why study health and illness in a group of people who don’t see a doctor?”
Well, that’s easy to answer. It is well known that many people hate going to the doctor or have a phobia of white coats. There are also people who, because of their advanced age, where they live, because they have no time for anything or for any other reason rarely visit the doctor (sometimes a private doctor and hardly ever in the public health system). Additionally, many people suffer from non-serious diseases (e.g. senile tremor) and do not see the doctor when they have a clear diagnosis. Many simply do not know that they have a disease. In short, many people that have or might have diseases never set foot in a surgery and therefore do not appear in the medical records, or if they do see a doctor, they do not follow the advice given, or attend periodical check-ups. The people who pass most unnoticed in these records are those are suffering from the initial stages of a disease, or non-serious chronic diseases; also, very old people who are uneducated or do not worry about their health. For these and other reasons, it is necessary to carry out studies on the whole population in order to detect health aspects that cannot be obtained from the medical records. A typical way of performing population-based studies is through national health surveys. In Spain a National Health
Survey is performed periodically, and is incorporated into the European Health Examination
Survey. A considerable number of citizens take part in these periodical surveys, providing regular information about their health, illnesses and associated aspects. But these surveys only reflect what is confessed by the participants – many people do not relate all of their ailments, or do so inaccurately (like in political polls). That is to say these surveys only allow a broad view of the state of health of the population, but not accurate biomedical studies
71
.
69
Bermejo-Pareja, 2007, analyse this problem and give examples about the high percentage (more than 30%) dementia cases missing from the medical registries in developed countries; the same is true with other chronic neurologic disorders ( Browson et al 1993 ).
70
The word, epidemiology, has a Latin origin: epi (above), demos (population), logy (knowledge); it is of
Spanish origin. It was used in 1588 in a treatise on the Black plague ( Peste Negra ) in Spain and a Spanish text in
1822 “Epidemiología en España” ( Epidemiology in Spain ) was the first formal book of epidemiology ( de Irala-
Estévez et al, 2004), as the prestigious dictionary of epidemiology (Last, 2001 ) recognised. The main data of population-based surveys are reviewed in Koepsell & Weiss, 2007 ; the population surveys in neurological disorders are the subject of several monographs ( Batchelor & Cudkowitcz, 2001 ; Nelson LM et al, 2004) .
71
General health population surveys with national representation are generalized studies in developed countries.
In USA they have a long history ( NHANES, 2013-14 ) and in this country the survey is associated with an elementary medical examination. In Spain, the “Encuesta Nacional de Salud” (Spanish National Health Survey)
38

Let’s move to the area that interests us: “why population-based studies on elderly people?”
This is because it is well known that the elderly suffer from medical under-diagnosis of chronic diseases for numerous reasons: isolation, poverty, mobility problems, and lack of education, among others. The under-diagnosis of dementia, Alzheimer’s and Parkinson’s and other neurological diseases is universal, as has been confirmed in population-based research and even in death certificates
72
. An example: in a sub-study of the NEDICES cohort, performed in Spain, on carers of patients with dementia, it was found that the majority rightly complained that it is a continuous and undervalued job (many carers need psychoactive drugs to cope with it), but nearly 25% of them, a very substantial percentage, hardly acknowledged the workload of this care (for 2.3% it did not exist; 11.2% called it very light; 9.6%, light; they thought that elderly people with dementia should be cared for like little children). If we had not carried out this study, we would have thought that the feeling of burden associated with caring for a person with dementia was universal
73
. Today, 20 years later, these percentages might be different. So population-based studies give a more complete idea of aspects of diseases in the elderly that are not picked up in a medical environment, and also, as we shall see in the next chapter, they allow the investigation of possible causes or RF of chronic diseases
74
.
From what has been explained, it is understood that it is impossible to achieve accurate medical records for the chronic diseases of the elderly, many of which overlap, and do not always result in visits to the doctor. For these reasons, in order to determine their true presence in the population ( prevalence ) and their appearance ( incidence ), population-based studies are needed (to avoid the bias of not including those who do not see a doctor or stop doing so). And this is done all over the world, including Spain. Studying certain aspects of health with biomedical criteria is achieved by a transversal study of a population (i.e. the whole population in a short period of time). But to detect the incidence (new cases of the disease) it is necessary to perform another kind of study, called prospective . So to calculate how many people in a country have a dementia, the practical way to proceed is to study a reduced population (several thousand) and to relate the results to the rest of the population.
And the best way is to perform studies on various populations in the country, combine the findings, and extrapolate the results to the whole population
75
. But calculating how many and its European part, is performed by the Ministry of Health every four years. It is a great work; the last published (2011-12) surveyed more than 26,000 citizens. It possible to obtain its main data free online
(www.msssi.gob.es/estadEstudios/estadisticas/encuestaNacional/encuestaNac2011/PresentacionENSE2012).
72
The under-diagnosis of elderly disorders includes cognitive impairment ( Colsher & Wallace, 1991; Wallace &
Woolson, 1992 ) and dementia ( Lang et al, 2017 ) and is a universal fact. The detection of chronic neurological disorders in the population requires complex methods ( Wallace, 1992 ). Historically, Bruce Schoenberg, an excellent American epidemiologist, director of Neuroepidemiology (NIH), performed a pivotal survey to detect
PD (much more prevalent than supposed according to the medical registries) ( Schoenberg et al, 1985 ). In his visit to Spain, he gave many lectures and was the leader on one the first population-based neurological surveys with the neurologists of the UH12O. In his memory( his death was premature) a valuable monograph was published ( Anderson et al, 1991 ). The finding of under-diagnosis of chronic neurological disorders has a new example in senile tremor in NEDICES ( Benito-León et al, 2004, 2005 ). Its incidence and prevalence are very much higher than previously thought based on the medical registries. The under-diagnosis of NDD also affects death certificates ( Ganguli & Rodriguez, 1999 ; Romero et al, 2014 ).
73
74
Bermejo, 2004; pp: 224-231; Bermejo F et al, 2002 and Rivera-Navarro et al, 2008 .
These studies in the elderly date back to the previous century ( Wallace & Woolson, 1992 ), although they are performed at all ages (Browson et al 1993 ).
75
There are many dementia prevalence surveys in Spain. The largest that has been performed, by only one team of neurologists, is NEDICES ( Bermejo-Pareja et al, 2009) . de Pedro-Cuesta et al, 2009, implemented a
39

cases of dementia appear in a population ( incidence ) is a more difficult issue. A cohort or prospective study is needed. This means studying a certain population to determine how many cases of dementia there are in this population and then following the population over several years with periodical check-ups in order to detect new cases of dementia. The best known study of this kind, as mentioned in a previous chapter, is the Framingham study, which was initially designed to study the RF of myocardial infarction, which was the cause of many deaths in the US in the 30s and 40s. The study discovered the importance of obesity, high blood pressure, consumption of tobacco, and physical inactivity as RF for CVD. But this study has been used to detect other diseases such as dementia, as was explained in the previous chapter
76
. Much more could be said about these studies: how they are done, the difficulties and high costs, and the capacity to attribute their findings to the whole population of a country, but what has been described gives a rough idea of their utility. multicentre survey in several Spanish regions with the same protocol for dementia detection and diagnosis. A nice calculation of the prevalence of dementia all over the world has been performed ( Prince et al, 2013 ).
76
Many surveys confirm that RF control produces a decrease in morbidity and mortality of CVD ( Ergin et al,
2004; Jones & Greene, 2013; Feigin et al, 2016 ; GBD 2016 Risk…,2017 ).
40

These days it is simple to detect the causes of infectious diseases from the AIDS virus to the cholera bacillus. In some chronic infections (leprosy and tuberculosis), finding the infectious agent is more complicated. But, since the 19 th
century the Koch postulates
77
which regulate their diagnosis, have existed. However, infectious agents no longer causes the epidemics of the developed countries – the epidemiological transition has taken place. Nowadays their main health problems are chronic or complex: diabetes, obesity, CVD, cancer and dementias, whose causality is very complicated. In order to unravel their causes we must resort to more complicated studies than those used for infectious diseases
78
. The point is, these 21 st
century epidemics in developed countries do not have a single cause, but rather a set of causes or causal factors called risk factors (RF), whose concurrence determine the disease. This multiple causality is an important chapter in epidemiology ; in fact it represents a branch: analytical epidemiology . Its discussion, with the implications for the philosophy of science, is outside the scope of this monograph
79
.
In broad terms, it can be said that RF and protection factors (PF) interact in the development of complex diseases . An RF does not necessarily lead to a disease, but rather increases the likelihood of its developing, and the opposite is true of a PF
80
. The RF can be modifiable
(tobacco consumption or obesity) and are the ones we shall discuss in the pages to come. But if we return to table 3 (10.1), we see some non-modifiable RF (age, sex, certain genetic factors, which for the moment cannot be altered, although in the future this may be possible).
Also, we shall often refer to the term marker or biomarker (a marker that is biological in nature), which is any type of feature associated with an RF or disease. Thus, height has a slightly positive association with intelligence (the taller, the more intelligent): it can be said that height is a marker of intelligence in the population (though it is a very weak marker), and it is clear that height is not the cause of intelligence, nor does it have any effect on intelligence. It is not an RF, only a marker. The deposition of amyloid-beta (
$ ȕ LQWKHEUDLQ is a marker of AD – it marks or accompanies the disease. When its presence in the brain increases, so does Alzheimer’s. Thus it is a marker, and for many scientists it is an RF or causal. The same is true for level of education and risk of dementia and AD, as we mentioned
77
The Koch postulates (19 th
century), enunciated by this author are deterministic characteristics of infectious illnesses. In very brief, they are: the organism (bacteria) must be present in each case of illness; it must be obtained from the patient and cultivated in the laboratory; if inserted in susceptible animals, it must cause the illness and it must be obtained from this animal and identified. The Koch validity postulates have been adapted in 20 th
century, mainly for chronic diseases ( Evans, 1976 ).
78
See Browson et al, 1993 ; Ben-Shlomo & Kuh, 2002; Darnton-Hill et al, 2004; Waterland & Jirtle, 2004;
Lango & Weedon, 2008; GBD 2016 Risk…,2017. This last study is a g lobal, regional, and national comparative risk assessment of 84 behavioral, environmental, occupational, and metabolic risks or clusters of risks, from
1990–2016 with a systematic analysis for the Global Burden of Disease.
79
Analytic epidemiology discusses the causes of sickness of every kind (biological or other). This type of epidemiology by means of case-control, cohort, and clinical randomized trial (CRT) studies, searches for objective evidence, which is the basis of evidence-based medicine (see Martínez-Martín & Bermejo-Pareja,
2000 ; Sackett et al, 2000; Candelise et al, 2007 ). Clinical epidemiology studies the diagnosis, treatment and prognostic aspects of diseases ( Fletcher et al 1988 ; Rothman et al, 2008 ).
Cause-illness research is a subject of scientific and philosophic importance with immense debate: Occam, Kant,
Hume, Bayes, Popper, and Rothman among many others. The British philosopher, Mackie, 1973 , gave many examples of the problem, and from the epidemiological side, Susser, 1991 and Rothman et al, 2008 debate this subject with authority.
80
RF belong to analytic epidemiology (see FN # 74) . In Spanish, we recommend the text of de Irala-Estévez et al, 2004 . In English , Susser, 1991; Last, 2001; Rothman et al, 2008 are nice examples .
41

in chapter 6. It is difficult to know if a variable (or characteristic) is an RF, a marker, or both.
Also, being an RF or a marker does not necessarily mean it is the cause of the disease. This confusion shows the difficulty studies have in identifying potentially causal RF. To do this, there are some rules or postulates proposed by Hill
81
, which are summarised in table 3
(10.1). And figure 15 (10.1) shows graphically the interaction of multiple causes that can lead to the syndrome of dementia. This graphic should not be seen as a fixed picture, but rather as a chart that varies from person to person (some will have a greater genetic load than others; some people have a greater cognitive reserve than others). So the chart is orientative, dynamic, and different for each person.
Table 3 (10.1). Criteria for establishment risk factors (RF) in illness&
(Main conditions)*
1) Temporal gradient (Possible RF must precede the illness)
2) Strength of the association (Higher association greater possibility)
3) Consistency (The association persist with different experiments and with different population and researches)
4) Gradient effect or dose-response effect (Grater RF exposure higher effect)
5) Biological plausibility (Cause-effect relationship can be biologically explained)
6) Coherence (Extent to which a hypothesized causal association is compatible with preexisting knowledge)
7) Specificity (Precision with which one variable will predict the occurrence of effect)
8) Experimental evidence (in animal o RCT)
& Very much synthetized form Hill, 1965 and with Susser, 1991, addictions and explanations.
*Main conditions for causal inference of the possible RF (the first three are the most important)
81
See Hill, 1965.
42

Figure 15 (10.1).
AD risk and protection factors (Causal pie)
Genetic FR could be 40-50% of the pie, later “ageing” according to several authors; other denied this
RF (Peto et al, 1985; Nelson et al, 2011). Environmental factors could be 35-50%. Cognitive reserve and physical activity are the main PF, life style (diet and others are also important as well as CVFR control). The pie must be interpreted as a standard and flexible proportion of risk and protection factors that change in every person and in each person and along the life.
By observing table 3 (10.1) it can be deduced that the only sine non qua point to infer the causality of an RF is temporality (the RF must be present before the disease begins) and the rest are not hugely necessary. But a statistically strong and consistent association (observable in various studies performed by different researchers and in different populations) is of great value, as is biological plausibility (it can be explained biologically). It must be remembered that many hypotheses on causality that have been held for years crumble away little by little
(or suddenly) with new evidence. This is how science advances. All this leads us again to the
K\SRWKHVLV RI WKH FDXVDOLW\ RI $ ȕ LQ VSRUDGLF $O]KHLPHU¶V V$' 7KH WR[LFLW\ RI WKLV deposition as a cause of familial AD was biologically plausible because the genetic disorders increased the probability of over-
SURGXFWLRQRI$ ȕ DQGWKLVZDVDSSOLHGWRV$'+RZHYHU systems biology maintains, and the failure of anti-
$ ȕ GUXJVYDFFLQHVVXSSR rts the assertion that it is only a marker of sAD, and not a causal factor
8283
82
The “causal pie” is used in epidemiology ( Rothman et al, 2008; Wensink et al, 2014). See Chap # 22 and 23 for the discussion of RF and their analysis. The causal pie represented in this Chap is schematic.
83
See Chap # 18 and 22e for more details.
43

Heredity and genetics are difficult fields (in general, and specifically in AD)
84
. Its data and concepts are changing quickly
85
. Nevertheless, genetics needs some attention to be understood, but it is necessary to put the effort in it, because it is increasingly a subject with practical and theoretical challenges that is integrated in our cultural background. Also, in the future it could be an area of debatable privacy (many people are reluctant for their genetic background to be a public matter; e.g., if this information were to be known by an insurance company).
This text will not discuss the tantalizing arena of the biology of heredity and genetics, because it is outside the scope of this book. However, it is worth stating that this century has modified the Neo-Darwinist hypothesis that all heredity is in our genes (that is to say the well-known double helix of DNA inserted in the nuclei of cells). Obviously, our heredity is in them, but it is more complex than that. There are many forms of biological heredity
86
. Heredity is clear if there is a specific gene error that will determine familiar disorders (e.g., Huntington chorea or some myopathies) but very complicated in complex traits (height) or diseases (diabetes,
Alzheimer’s, NCD).
The advances of the genetic techniques that have evaluated thousands and hundreds of thousands of human genes in the complex diseases (NCD) and have found a constant: genetic errors found in them only explain a portion, in general less than the suspected heredity obtained by clinical methods (pedigree) in the systemic disorders evaluated
87
. How to explain these results?
Perhaps it isn’t the moment to explain these findings. It’s more realistic to remember a wellknown genetic story. We must start with classical or hard genetics and the fascinating history of the discovery of the structure of genes: the double helix of DNA. Nowadays this discovery seems mundane, but in reality it was an historic feat comparable with reaching the summit of
84
See Chap # 4 and the reviews of Bertram et al 2004, 2010, Bekris et al, 2013, Chouraki & Seshadri, 2014,
Calero et al, 2015 and Gaiter et al, 2016 . The ongoing advances of AD heredity by genetic new tools (GWAS) justified the continuously updated website ( AlzGene web: www.alzgene.org
). Besides ApoE4, around other 20 alleles of AD risk have been described with very little risk for sAD ( Lambert et al, 2013, Naj et al, 2017) . The
Lambert et al, 2013 , study included several genetic databases: Alzheimer’s Disease Genetic Consortium
(http://www.adgenetics.org/), Genetic and Environmental Risk in Alzheimer’s Disease Consortium
(http://alois.med.upenn.edu/adgc/), International Genomics of Alzheimer’s Project
(http://consortiapedia.fastercures.org/consortia/igap/), that incorporated 17,008 AD cases and 37,154 controls.
Another important database is CHARGE ( Cohorts for Heart and Aging Research in Genomic Epidemiology; http://www.chargeconsortium.com/). Protective alleles for sAD have been described in the PPA gene ( Jonsson et al, 2012 ) and TREML2 gene ( Benitez et al, 2014 ). There are GWAS analyses not only in clinical AD cases, but also in pathological AD cases ( Beecham et al, 2014 ) with some different findings.
85
The new methodology CRISPR-Cas9 ( Singh et al, 2017 ) that allows easy editing of DNA sequences or cutting them and inserting new sequences (for humans or for other living beings) rapidly puts us in a science-fiction future. Currently, it is too early to know the possibilities of this new genetic technology in the AD field, but nowadays there exist brain “organoids” built in laboratories (“ brains in a dish ”) from stem cells for the study of genetic defects in neurons ( Mason & Price, 2016; Mungenast et al, 2016 ).
86
See the outstanding article of Shapiro, 20017 (living organism read-writes its own genome) and Szyf, 2015 that shows how the parental environment may modify the phenotype of the new being through epigenetic mechanisms.
87
Consult Vinkhuyzen et al, 2013 , which explains possible reasons for this ‘missing’ heritability; Zuk et al, 2014 insist on this subject and give more explanations.
44

Everest (also devalued these days as it is almost accessible to tourists in good shape)
88
. The feat was worthy of a Nobel Prize in 1962
89
and the discovery led to the race, starting at the beginning of the 80s, to sequence the human genome (Human Genomic Project), between an international consortium, financed with public money, and a private company, Celera
Genomics , led by the multifaceted Craig Venter. Who won? It was a draw. Both teams published their discovery in the same year, 2001, in highly prestigious journals: the international consortium in the British journal Nature ; and Venter’s team in the US journal
Science
90
. When the genome was sequenced, the sensation spread that a great scientific victory had been achieved, which would soon reveal the genetic origins of many diseases and the aging process. Also, it gave neurologists the hope of new discoveries about neurodegenerative diseases (NDD). The so-called Decade of the Brain had just ended, an initiative promoted by the US Congress, in which heavy investments were made in research into incurable neurological diseases. It is worth remembering the disproportionate number of genes in our DNA that are related to the brain, an organ weighing hardly 1.5 kg, as compared with the 60-90 kg of the rest of the body, and yet, more than a third of the genes are devoted to its formation and functioning. As we have pointed out, the sequencing of the human genome seemed to be a landmark that, in little time, could change the outlook for neurological diseases (including AD), which after 100 years of history, was bleak
91
.
We longed to see genetics and the neurosciences achieving the miracle of enhancing therapies for NDD. But, in reality, these wishes did not come true. The fact is that DNA has around 3 billion base pairs, and the smaller mitochondria contribute another 16,000 (almost exclusively from the mother).
The number of genes is not known precisely, but there are thought to be about 20,000, and their functioning is complex as they interact with each other ( epistasis )
92.
It is known that genes have the key to producing innumerable proteins, lipids, enzymes, and other compounds, but their investigation is very complex and has given rise to what has been called the sea of “omics” (genomics, proteomics, and so on – an ocean that will lead us to understand the functioning of the cell in the complex field of systems biology )
93
. It is worth making a simile: the discovery of the human genome is like knowing the cards in a gigantic pack; it is as if we had identified each card (gene) in an enormous deck of more than 20,000 cards, but we did not know which game the cards were playing, or the rules of the game.
There are a lot of cards, and where are the rules? They have to be discovered little by little... a task of astronomical proportions. It has turned out that knowledge about the human genome isn’t the “book of life” as it has ingenuously been called. We have only managed to ascertain the cards (genes) of the immense pack, which does not allow us to know which card game is being played by genetics in heredity and in the majority of human illnesses. We don’t know
88
See the history described by one of the Nobel Laureates (Watson, 1986 - in his Spanish version)
89
The 1962 Medicine Nobel Laureates were Francis Crick, James Watson and Maurice Wilkins for finding the underlying cause of the double helix of DNA molecule. Rosalind Franklin, a crystallographer, who first
“photographed” the double helix, did not receive this award because she died prematurely (the Nobel Prize is only for living people).
90
91
International Human…, 2001, in Nature, and Venter et al, 2001, in Science
The difficult history of Neurology (traditionally with few therapies) is explained in many texts (e.g., McHenry,
1965) ; the Decade of the Brain (1980-90) was initiated because of the immense costs of neurological disorders and approved by US Congress ( Ringel, 1999 ). Bermejo FP, 1999, comments on the repercussions in Spain .
92
Epistasis is the co-action between genes that can multiply their effects. See Combarros et al, 2009; Gusareva et al, 2014 to understand epistasis in AD.
93
See Kitano, 2002; Wood et al, 2015; Lista et al, 2016.
45

the rules of the game in order to be able to win the game and understand what the “book of life” really says. Clearly, the discovery of the human genome, which came at a huge financial and scientific cost, has led to many basic biological advances, but no notable biomedical advances. Medicine is a practical discipline, for which this feat has only meant significantly better understanding of rare diseases, but hardly any advance in the genetic understanding of
NCD: myocardial infarction, stroke, diabetes or AD
94
. Why? This will be explained later.
Let’s return now to where we left our tale. Hard heredity is not the entirety of human heredity
(the error of last century) – there are other mechanisms that were not considered: one of the important mechanisms is epigenetics or soft heredity (but there are others of lesser importance and high complexity, which we are not going to go into)
95
. But, “what’s all this about epigenetics, please?”
Epigenetics is the study of certain hereditary mechanisms with which the phenotype is modified (let’s call it people’s appearance) which are not transmitted by sequences of DNA
(genes). It is soft heredity , normally transitory (as opposed to the hard heredity of genes) – it can appear at one moment in life and then disappear, although its actions can be important for the individual and his children
96
. An example: hard heredity allows bees to inherit their appearance and participation in the hive, but belonging to a particular caste (queen, worker) is determined by epigenetic mechanisms
97
. Epigenetic mechanisms allow the linking of the environment with the genes. Modifications of the environment (diet, tobacco, or environmental stress, i.e. poverty) allow it, through biological epigenetic mechanisms, to act on the genes and modulate their action
98
. Many epidemiological data and data from experimental animals confirm this. In principle, these mechanisms do not produce lasting changes in the genes, although they can be transmitted over several generations; they act preferentially on the foetus when it is in the womb, although they can act in infancy, and above all before puberty. As an example: exposure to starvation during pregnancy can generate a propensity in the child to diabetes, metabolic diseases or AD
98
. Even though at
94
It is true that genetics underpin several of the molecular pathobiologies in NCD, but only minimal practical medical consequences have been determined (e.g., the minimal advances in one of the most important diseases:
CVD – leading cause of death in the world -Thanassoulis & Vasan, 2010) .
95
See Danchin et al, 2011 . Besides genomic heredity, there are other types of human heredity: epigenetic, ecological, cultural and others. We shall only mention cultural heredity. In the Neolithic era, humans started herding, and with herding began milk and dairy intake. People whose milk intake was high after many years developed a genetic modification: a new genetic allele that enables the milk drinker to assimilate milk lactose.
This allele is frequent in Nordic European countries; the populations that do not have this genetic modification must take only lactose-free milk from the shelf ( Curry, 2013 ).
96
See Chap # 4. Even though epigenetic mechanisms have been known from the middle of the 20 th
century, epigenetics has gained strength in the 21 st
century. Reik & Walter, 2001 and Waterland & Jirtle , 2004; Jablonka
& Raz, 2009; Jablonka & Land, 2011 analysed the basic epigenetic mechanisms of the transmission of epigenetic information from gametes to foetus (mainly by the maternal line). Petronis, 2010, discussed the epigenetics of complex diseases. Pembrey et al 2014, the mechanism of transgenerational heredity. Duncan et al,
2014, reviewed epigenetics in plants and animals, and Hanson et al, 2011, in humans; Wang et al, 2013 and
Lardenoije et al, 2015 reviewed epigenetics in aging, NDD and AD; Mastroeni et al, 2011, Lunnon & Mill, 2013 and Bennett et al, 2015, specifically in AD. Other interesting epigenetic works: Mitchell E et al, 2016, which reviews the epigenetics of behavioural traits. Maloney & Lahiri, 2016 , explained that dementia is a longstanding process from the epigenetic standpoint.
97
98
See Palatano et al , 2012 .
Foetal starvation produces the well-known ‘thrifty phenotype hypothesis’ ( Hales & Barker, 2013 ). If the thrifty child had access to a food abundant environment, he could have a metabolic derangement that would facilitate DM2 and other NCD. See also Chap # 22a
46

first it was thought that epigenetics would be a theoretical discipline, it has not turned out that way. We’ll see its practical aspects in AD. Let’s analyse another subject.
“Which neurological processes does epigenetics influence?” What does epigenetics have to do with AD? The short answer is: the epigenetic mechanisms participate from the start of the NS in neurogenesis , brain development and learning, and in several neurological diseases: autism, depression, psychosis, NDD and AD. In AD, epigenetic modifications are observed in the brain areas where pathological alterations of AD are found, as well as in several of its metabolic processes: AD markers – A ȕ
, tau, cellular inflammation, oxidative stress , and mitochondrial alterations
99
.
Figure 16 (11.1).
Main epigenetic mechanisms
This figure schematizes three epigenetic modifications: DNA methylation, histone acetylation, and the actions of micro RNA (non-coding).
Abbreviations and explanation: Non-coding: refers to the action of RNA that does not intervene in the codification of proteins, only in genetic transfer regulation.
Transcription means the genetic information data transfer from DNA to RNA.
Translation means: the DNA data incorporation to proteasomes by the messenger RNA
This figure is a simplification and modification of figure 1 of Lardenoije et al, 2015.
Let’s cut this explanation short and look at figure 16 (11.1), which schematises the epigenetic mechanisms in the genetic tangle. DNA, contained in the genes, is located in the nuclei of neurons (as in other cells), and has to transmit its genetic message in order to manufacture proteins and other substances. But the DNA does not come out of the nucleus (it is protected by its precious structure) – it sends a messenger to the cellular protein factory ( proteasomes ).
DNA, like the post office, needs a postman to carry the messages to their destination – messenger RNA (a special copy of DNA). “And what does all this have to do with
99
To better understand this subject you can read: Mastroeni et al, 2011; Wang et al, 2013; Bennett et al, 2015, and Lardenoije et al, 2015 , who reviewed the epigenetic mechanisms in the evolution of the NS, aging, NDD and AD.
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epigenetics?” Well, a lot. Epigenetics studies the modifications that can happen in the DNA
(genes), in the substance that binds them (the supporting conglomerate of the genes called histone ) and in certain fragments of the messenger RNA. And in the messenger RNA’s journey through the cell, it can drop some of its portions (the pressured postman can drop some of the letters from his bag, especially if they aren’t registered). These “dropped” fragments of messenger RNA are known as microRNA (miRNA), as they are a small part of the RNA molecule, with only 18-22 amino acids . So, DNA, histones and miRNA can be modified: the DNA is methylated, the histones are acetylsed and the miRNA are modified.
Someone will ask: methylation and acetylation, are they like when a peeled apple oxidises and changes colour, or when wine turns to vinegar? Yes, apart from the distances, it’s like that.
These changes can deactivate the genes or make them hyperactive. That is to say, the epigenetic modifications don’t change the genes, but switch them on or off (change their normal activity) in a more or less transitory manner
100
. And who methylates them or modifies them? Several agents.
The first agent that can make epigenetic changes is the parents, or rather, the parents’ gametes
(sperm and ova) that transmit their genetic information via the DNA, which carries the atavistic inheritance of preceding living beings including humans (genes), but also brings their recent perception of environment, fundamentally the metabolic environment. To simplify: the genes (DNA) represent the global biological information for constructing a new being. The epigenetic changes are information from the preceding generation (or the grandparents), which the parents transmit in order for the new being to adapt to what its predecessors experienced in their environment and consider (biologically, of course) is going to be beneficial for the new being. This intelligent genetic mechanism is given the name imprinting
(an imprint that is established in a genetic allele) – it moulds genes and other genetic structures
101
. This epigenetic imprinting is not only performed by the parents’ gametes, but also by the environment (via the placenta) that surrounds the new being, or when this happens during childhood. The environment can’t modify hard heredity (the DNA of the genes), unless it is over many, many generations according to the neo-Darwinian hypothesis. But epigenetic mechanisms can adapt this hard or stable heredity (DNA) through small changes in the genetic structures (soft heredity), in order to suit them to the existing recent environment. And environment is everything: nutrition, education, physical exercise, external agents (from air pollution to medications) and many others. To sum up, atavistic heredity (genes) is adapted to the current environment through epigenetic mechanisms in which various gene networks intervene
99
.
100
Review FN # 96 and # 99.
101
We discuss this subject in Chap 4. The geneticists put the risk between 28%-80% (e.g., Naj et al, 2017 ). The risk of AD in the first-degree (siblings) could be 2-3 times higher than in controls ( Cupples et al, 2004;
Silverman et al, 2005) but this depends on the age and sex of the AD proband case .
Twin studies are difficult to evaluate because twins have similar genetic background and analogous environment. The studies showed diverse risk data (30-79%); probably the best investigation is the Sweden Twin Study with high number twins included
(more than 11,000) and with analyses of the incident AD; the genetic risk was 48% ( Pedersen et al, 2006 ).
Margaret Gatz, the Californian leader of this study, quantifies the risk as nearly 50% ( Gatz, 2005 ). The problem is that this substantial genetic risk is not observed with genetic evaluation (GWAS and others) of the genome, this fact it is called missing hereditability.
Although, the Rotterdam study showed that persons with ApoE4 and low risk genetic alleles suffer identifiable high AD risk and early age onset of their dementia ( Van der Lee et al,
2018).
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“What a rigmarole in order to say nothing about heredity and AD”. Yes, it’s a rigmarole, but we believe it’s necessary.
Let’s move on to the facts about heredity and AD. As we have described (Chap 4), knowledge about heredity has divided AD into two types: fAD represents 1% (genetic errors in one of three known genes) and the vast majority of cases (99%) are sAD, in which genetic, epigenetic and environmental factors contribute to its genesis. Only the presence of the allele
ApoE4 is a clear RF of sAD (although there are other genetic RF and PF detected of minimal importance).
The question that everyone wants to answer is: how much of sAD is hereditary that is not hereditary in the strict sense? because it seems logical to suppose that there will be something hereditary like in other diseases (NCD); and how important are environmental factors in sAD?
In all chronic diseases (cancer, arteriosclerosis, diabetes) the proportion of heredity has been investigated by traditional methods: family studies (pedigree), twin studies and others. The
21 st
century has added the sophisticated genetic methods of the genome (GWAS in the last 15 years). If we confine ourselves to the traditional family studies in AD, hereditary factors would mean around a 50% risk of suffering from the disease, although the data are very varied
101
. This percentage is based on studies of first degree relatives of patients with sAD, who have a greater risk (double or somewhat more) than people who do not have a parent with AD, and in twin studies (which are more difficult to interpret) the risk is high; the other
50% of the total risk would be environmental factors, but the debate on this subject is heated and consensus is dubious
102
.
The problem of heredity in sAD is exacerbated with the appearance of genomic studies
(DNA) of the entire human genome. What do you think – is more or less genetic risk found than with the traditional studies? The results will surprise both you and the geneticists. The genetic risk in the studies of the human genome with these studies on the “book of life” is less than in the traditional studies: only a little over 30%. This problem is called missing heritability
103
. And something similar has happened with other NCD (diabetes, obesity). How to explain this?
Explanations: a) the clinical calculations of genetic risk could be overestimated; b) the sophisticated genetic techniques (GWAS and others) miss risk alleles or don’t count other risks that could exist; c) epistasis between the risk genes that is unknown; d) epigenetic heredity is not usually included in GWAS. The reality is that we don’t really know
103
.
Right, are there any practical consequences of epigenetics in AD apart from the understanding of its effects? The answer is yes. The methylation of DNA or the characteristics of miRNA can be markers for the diagnosis of sAD. miRNA are small molecules that are distributed throughout the humours (blood, CSF, saliva). Their modification could have preventive
102
See Grant, 2005, and Gatz, 2005 for one of the several discussions . Ashford & Mortimer, 2002, think that sAD is mainly hereditary; a more accurate opinion is that of Wingo et al 2012.
103
See the tantalizing articles of Maher, 2008 and Manolio et al, 2009 of epigenetic in several neurologic disorders, and in AD by Ridge et al, 2013.
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potential: in foetal care, lifestyle (diet, exercise), reducing the risk of AD and also in the development of drugs as has already happened in haematological cancers
104
.
And to finish, another difficult question: what is optogenetics (it sounds very strange)? Can it contribute something to AD research? It has been discovered that light can activate certain proteins and this is being investigated intensely in many laboratories (in transgenic mice).
With complicated techniques, light-sensitive proteins could be inserted in the hippocampus, which would activate memory mechanisms. Perhaps in the future these could be used to treat memory loss in AD
105
. We are approaching science fiction, as with driverless cars, which will be common in less than 20 years. We’ll see…
104
miARN are spread in the fluid (blood, saliva, CSF) and can be used as AD biomarkers ( Keller, 2016;
Danborg et al, 2014 ; Van den Hove et al, 2014; Giau & An, 2016 ) and for therapy ( Adwan & Zawia, 2013 ), including anti-miARN drugs ( Zhao et al, 2016 ). Drugs that modify epigenetic markers in histones and in DNA methylation are approved in USA for hematological cancers, and in the future could be tried in AD ( Lock, 2013 ;
Wang et al, 2013; Whalley, 2015 ).
105
See Cho & Li, 2016.
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It was the determination of a mentor, Kraepelin, to promote his protégé that explains the fact that we now know Alzheimer’s disease by this name. In 1901, the psychiatrist and pathologist
Alois Alzheimer ( figure 17 12.1) was treating a patient called Auguste D, the wife of a railway worker, who at the age of 51 began to show signs of dementia (memory disruption, progressive cognitive decline with aphasia , and hallucinations). Alzheimer examined her brain tissue with a microscope and found an unknown lesion: the presence of threads in the shape of tightly tangled springs, which had the appearance of balls of wool ( figure 1812.2).
Figure 17 (12.1).
Classic photograph of Alois Alzheimer
Figure 18 (12.2).
Original drawing of neurofibrillary threads (neurofibrillary tangles -
NFT) by Alois Alzheimer
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When he observed these neurofibrillary threads, which are known in medical terms as neurofibrillary degeneration (NFD), Alzheimer did not believe he had found a new disease
( figure 11 -6.8). A colleague, Fischer, had already described the presence of senile plaques
( figure 10 6.
7 ) in the brain as a characteristic histological feature of senile dementias
106
.
Alzheimer thought that the neurofibrillary threads were just another manifestation of dementia, which, at that time, was attributed to the lack of cerebral blood flow due to arteriosclerosis of the arteries that irrigated the brain. However, his powerful boss, Professor
Emil Kraepelin ( figure 19- 12.3) did not have the same opinion. Kraepelin, the author of a famous treatise on psychiatry, was held in high esteem for his biomedical psychiatric nosology (opposed to the psychoanalytical psychiatry of Freud)
107
. For him, mental illnesses were biological alterations of the brain, and psychiatric diseases were well-defined entities.
Fischer, the discoverer of senile plaques (SP), belonged to the school of Pick, in Prague, a rival of the psychiatric school of Munich led by Kraepelin. For this reason, some authors have seen Auguste D’s diagnosis as an astute tactical move by the powerful professor for his protégé Alzheimer to be credited with the discovery of a new disease, and incidentally be awarded with a professorship in 1912. Many decades later, a study in the journal Science suggested that the diagnosis of patient Auguste D, the first case of Alzheimer’s disease, should in fact have been leukodystrophy (a very rare genetic disease)
108
. It will be difficult to ascertain this categorically, as we do not have the studies of the hippocampus, which is the brain structure specifically affected in AD and nor do we have the whole brain (only the histological preparations that Alzheimer used were recovered). From these old preparations used by Alzheimer, containing NFD and SP, we know that the case described was not a genetic form because the brain material contained in them has been studied genetically.
Alzheimer described another cases of pre-senile dementia , but it was a rare form where only
SP and hardly any NFD appeared
109
.
It is possible that Kraepelin was not being pragmatic and that he was being true to his essentialist conception of mental illnesses, which he conceived as natural, pathological and clinical entities, which were clearly differentiable by their biological features. Be that as it may, the addition of this new disease was a historical landmark as from that time senile and pre-senile (under 65) dementia were distinguished, the latter named by Alzheimer. This separation was to persist until 1978, but from the 30s, scientists began to doubt that its cause was a deficit in cerebral blood flow
110
. And this classification, in the forgotten chapter of the history of dementias, began to show cracks at the end of the 60s, when Anglo-Saxon
106
See Amaducci et al, 1986. It is interesting to know that Maurer, 2006 and Whitehouse & George, 2008 recently described, in the 21 st
century, the finding of the original documents of the first clinical patient protocol
(in German and Latin). These documents were missing for many decades in the Munich Institute of Pathology.
107
Derouesné, 2008, considered that the Kraepelin idea of the mental disorders and dementia classification is as if they existed as well delimited natural illnesses. In a historical note about Kraepelin, Engstrom & Kendler ,
2015, considered that he was the first author of psychiatric disease nosology. Previously, psychiatric and psychoanalytic orientations lacked biomedical background and were not propitious to the brain examination. The
Kraepelin School considered the mental diseases as brain disorders and their strict delimitation was possibly due to his didactic work as Kraepelin’s Psychiatry professor. Perhaps the neo-Kraepelinians have exaggerated his nosology strictness. Be that as it may, the birth of AD has generated great debate: Derouesné, 2008 ; Amaducci,
1986, 1996 ; Boller & Forbes, 1998; Whitehouse & George, 2008 , and Ramirez-Bermudez, 2012.
108
Amaducci, 1996. Neither author in our knowledge has rebutted his assertion .
109
See Graeber et al, 1997, 1998.
110
Bermejo et al, 1986 commented on the history of the VaD-AD separation. The text of Portera & Bermejo,
1980, indicated the future increase of dementia in Spain.
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pathological studies revealed that both dementias, senile and pre-senile, were a single disease from the pathological point of view. And this was agreed in 1978 at a meeting of the US
National Institutes of Health (NIH). From there came a specific clinical picture of the disease: loss of memory and slow, progressive cognitive decline, without motor signs, and with a pathology characterised by the presence of SP and NFD
111
. Also, the vascular hypothesis was withdrawn, its cause being attributed to neurodegeneration.
The Cartesian separation between AD dementia and the rest of the senile dementias has been questioned in the 21 st
century by pathological studies performed on the general population, differing from those done in hospitals. In the former, the pathological lesions observed in people affected by dementia are milder and heterogeneous, and there is a greater proportion of vascular lesions. In fact, in the population-base studies, what is diagnosed as idiopathic or sporadic (sAD) AD is a heterogeneous entity, where in most cases (75-80%) mixed lesions are present – vascular and AD-type. In reality, very few pure cases are found, with only ADtype pathology or only vascular-type (vascular dementia), or with other pure neurodegenerative diseases. For this reason, sAD has begun to be called dementia-
Alzheimer’s syndrome
112
.
The history of the birth of AD has inspired many investigations and a monograph
113
– proof of the scientific interest awoken by the disease. In fact, so much interest that, as previously mentioned, the histological preparations of Alois Alzheimer’s first cases have been analysed with modern biomolecular techniques. One thing seems clear: what Alzheimer described was not a genetic disease (fAD), nor did it have the genetic RF ApoE4. But rather, it would have been an (infrequent) pre-senile form of sAD. The specialists gathered at the NIH in 1978 were right about the unity of sAD. They were probably not completely right to rigidly separate ADtype dementia from the rest of the senile dementias, due to the frequent coincidence of vascular and other types of lesion found in them, as the controversy persists to the current day. However, they were completely right to determine that pre-senile and senile dementia with the pathology described by Alzheimer are one and the same entity. And this means, let’s say it once again, that AD is not formed in old age, but earlier, significantly earlier than
Auguste D’s 51 years, as will be shown in the course of this monograph, even though it usually shows its face in old age.
111
The pathological studies, such as the classic study of Blessed et al, 1968, contributed to demonstrate that, from a pathological perspective, there was no delimitation between the pathology of AD type dementias, beginning prior to or after 65 years. In a conference in the NIH of USA ( Katzman et al, 1978 ) a consensus was reached to call any presenile or senile dementia “AD-type dementia”, revoking the Kraepelin criterion half a century later.
112
The review of AD pathological findings of community studies ( Zaccai et al, 2006, Schneider JA et al, 2007,
2009; Savva et al, 2009; Attems & Jellinger, 2013), has shown a great lesion heterogeneity (mixture of several vascular lesions, AD type, hippocampus sclerosis and others). For this reason the term: dementia-Alzheimer syndrome has been proposed ( Richards & Brayne, 2010 ; Khachaturian & Khachaturian, 2015 and others). In addition, it is worth stating that there are quite numerous dementia cases without discernible pathology ( Boyle et al, 2013 ).
113
The old histological preparation of Alzheimer ( Graeber et al, 1997, 1998 ), conserved in the Institute of
Pathology of Munich University, has permitted its molecular study showing that the first cases described by
Alzheimer have no monogenetic error and are not ApoE4 positive. The monograph of Konrad Maurer & Ulrike
Maurer (in charge of the Alois Alzheimer house-museum), is translated into Spanish (2005).
53

Figure 19 (12.3).
Emil Kraepelin
54

Not always. In the vast majority of cases (75-85%), Alzheimer’s disease (AD) does start with slow, progressive memory loss – the form of onset known as “typical”. Sometimes (15-25%) it presents itself in another way (“atypical”): difficulty in speaking or understanding
( dysphasia ), or in finding one’s way in one’s neighbourhood, or in understanding writing, or various other difficulties which, in general, are shortly accompanied by memory loss. Rarely, the first sign of AD can be a behavioural disorder (extravagances or spending money absurdly) – this onset is more characteristic of frontotemporal dementia (FTD or Pick’s disease), emotional disorder (inexplicable irritability) or depression. In exceptional cases, the disorder can be psychotic (hallucinations) or motor (gait or other rarer forms). In brief, the presentation of AD is not as homogeneous as it could seem
114
. Nevertheless, AD usually starts with a loss of memory for recent events, forgetting everyday things, or words and names
( anomia ). Forgetfulness does not mean you are suffering from Alzheimer’s. From a certain age, many people fear that this is the case, so these days the most common reasons for visiting a neurologist are headaches and memory loss
115
. Fortunately, most people who visit a neurologist complaining of memory loss are not suffering from Alzheimer’s – they have other disorders, the most frequent of which are stress and depression. The typical profile of someone who sees a doctor complaining of memory loss is a woman aged 50-60, with many domestic jobs (care for elderly parents, sometimes grandchildren, as well as husband and children) and, sometimes, also having work outside the home, and who is not in a desirable financial or emotional situation. Yes, she has lost her keys, left a pan on the heat, or forgotten an important birthday. “Let’s see if I have Alzheimer’s” she says, and makes an appointment with the neurologist. When a full medical history is taken, it is clear that she does not have the disease, but rather an excess of work that makes huge demands on her memory, which means her memory for mundane events seems limited. It must be taken into account that remembering always requires mental effort.
This type of patient who complains of forgetfulness but does show memory disruption in a psychometric test is classified as having subjective memory loss
116
. Not often is this loss on its own a prelude to dementia or AD, especially when accompanied by conditions of stress, anxiety or depression. Some people find this hard to accept and often demand a scan (MRI or
CT) “in case I have something wrong in the head”. See case 1.
Case 1
A patient aged 46 who came to my surgery because he thought his memory loss affected his ability to work. He was an expert in computer programming and had just changed job (he was designing videogames); because of his complaints, they had performed a brain scan on him, and the results were normal. In his conversation and in the basic psychometric tests I observed
114
The typical AD clinical onset (revised with pathological and genetic data) is amnesic deficits (75-85%). See
Murray ME, et al, 2011; van der Flier et al, 2011 . Many neurological texts analyse the clinical beginning of AD:
Signoret & Haw, 1991 ; Parks et al, 1993. There are many reviews, Knopman et al, 2004; and Bermejo-Pareja et al, 2012 ; pp: 399-417 (in Spanish).
115
See Calandre-Hoenigsfeld & Bermejo-Pareja, 2011 as an example of out-of-hospital neurological consultations in Spain.
116
O’Connor et al, 1990, described the memory loss in several types of elderly subjects in a community-survey, and Benito -León et al, 2010 analysed the subjective memory loss in the NEDICES cohort
55

no anomalies. However, he claimed that these basic tests could not detect his memory loss, as he had always had an excellent memory, and at that time it was not as good. The psychologist performed a WAIS on him – a cognitive test that takes an hour to complete. The results were normal; in fact they were well above the average for the population, even though in the sections specific to memory he did not stand out so much. He still thought he could have
Alzheimer’s or something “weird” in his head. In the interview, I found out more about his life. His change of job had not been the only change in the last year: he had also divorced and started a new relationship, and had difficulties seeing his small children. I explained that in my opinion these changes could explain his subjective memory loss and his trouble dealing with his new job. But, he was not convinced; he responded with some irony that the new job was simpler than previous one and that he was doing it well but he had more difficulty remembering programs. The results may be normal but “I’ve lost memory, doctor”. I had to explain to him that it was possible – the psychometric tests compare a person’s performance with that of many other people of his age, with whom the tests have been validated, but not with that person himself. For this reason, I proposed to him that he should repeat the test in half a year, to compare him with himself. He returned a little over six months later and repeated the test, There was no reduction in memory performance. I told him that we could repeat the same test the following year in case some cognitive or memory decline had occurred. He left grudgingly, complaining about his memory loss and did not return to the surgery.
This case is an example of how stress can interfere with our memory. Sometimes it is difficult for us to accept our limitations, or rather, the limitations of our organism, which are revealed in excessively demanding or stressful situations.
We must bear in mind that in order to record events in the brain well, first we must pay attention to what is happening, and also recall past events; that is to say a mental effort must be made from time to time to remember the details of recent events, like a phone number or a birthday. Those who live with stress, anxiety or depression do not record facts in their memory because they are engrossed in multiple activities or, in the case of depressives; they dwell on their problems excessively and stop being interested in other matters. Along with this, there are many other causes for forgetfulness at these ages, such as subclinical brain lesions, especially vascular-type, which often pass unnoticed. It is rare that forgetfulness in people under 65-70 corresponds to the onset of AD, unless it is clearly progressive.
“Why are patients with Alzheimer’s forgetful but they remember their childhood well?” It’s complex: forgetfulness is the most striking part of memory disruption and the part that is best known outside the medical field. But there are various kinds of memory, as we shall see.
Forgetfulness is the impairment characteristic of the onset of the disease, but is not specific to it, as we have mentioned. The characteristic feature is the progressive increase and persistence of this memory decline over a long period of time (months or years) and that it subtly affects functional activities (such as keeping accounts). We must bear in mind that in old age, memory can be affected, as well as other cognitive functions, but cognitively normal elderly people can handle themselves well, even though their memory is not as brilliant as it was 3- 4 decades ago
116
. What is truly specific to AD is the progressive appearance of an inability to learn new events (difficulty with episodic declarative memory), which does not improve with cues or hints to remember what is being asked. But the deterioration of learning is not the
56

only impairment: typically at the onset of AD there are other associated subtle cognitive deficits, as we shall see later on.
“Ah, but is it right that there are lots of types of memory?” Well, yes there are, though some neuroscientists don’t really agree with the classification of the various types of memory that clinicians establish: psychologists, psychiatrists and neurologists. In fact, the existence of different types of memory has generated much research and passionate debate, but that’s another story. To put it briefly, for many scientists, memory is a specific capacity of living beings (from cells to mammals) which is necessary for the preservation of life
117
. It is a good concept, but too general for clinicians, who have a pragmatic job that forces us to evaluate the types of memory with diagnostic significance.
Table 4 (13.1) .
Mains clinic memory types and its cerebral networks (localization)
Memory Characteristics
Explicit or declarative
( conscious )
2-30 seconds min-days
Verbal Episodic years
Semantic
Implicit (non declarative, procedural)
(unconscious)
Motor acts years
Others
Duration
ProceduralPriming* Denomination
Pre-F *** & LTM & LTIF
Striatum Localization
sites as Cerebellum
Abbreviations; min: minutes; MTL: medial temporal lobule; IFTL: inferior-medial temporal lobule
*Unconscious facilitation; ** Classical conditioning; *** Cortex prefrontal and its cortical network
(frontal-temporal).
Synthetized from NCB, Bermejo-Pareja et al, 2012.
“What do neurologists mean when they talk about kinds of memory?” There are many classifications of memory. One that is well established, but is far from the only classification, is shown in table 4 (13.1). The three kinds of memory that neurologists evaluate most often are: immediate memory , also called primary memory : this is what allows us to remember several digits for a few seconds (e.g. a phone number), a short sentence, or some shapes. It is also known as working memory (although this has specific connotations of attention and concentration). This type of memory is not impaired in Alzheimer’s in the initial stages – it is only affected at the moderate or intense stages. In the initial phases, the kind of memory that is damaged is secondary memory , above all episodic memory, which confers the ability to recall everyday events and their location in space and time. Some authors subdivide this type
117
See Salthouse, 2003, 2012 , who reviewed elderly memory in the laboratory and in the everyday real world.
57

of memory into recent or short-term (hours or days) and distant or long-term (months or years).
So, in AD, the kind of memory that deteriorates specifically is recent episodic memory . When a patient is accompanied by someone who lives with him, the best way to evaluate the patient’s recent episodic memory is to ask him what he had for breakfast on the day of the interview or what he had for dinner the previous evening; if he cannot remember these facts in detail, there is a suspicion of an impairment of secondary or short-term episodic memory.
This kind of memory can be easily assessed in the surgery by simply stating 3-5 words (e.g. money, house, dog, humility), then after distracting the patient with questions for a few minutes, asking him to recall the words. A person with no cognitive deficit remembers three or four words. Not recalling a single word is a clear pathological sign; remembering only one suggests that there could be a defect in secondary memory. However, distant or long-term memory , which stores the events of childhood and adulthood ( autobiographical memory ), is not found to be clearly affected in the initial stages of AD. Often, distant memory (though partial or occasional) can persist until the very advanced stages of the disease. This dichotomy between the forgetting of recent events and the preservation of some distant memories surprises many families, as does the relative conservation of semantic memory , which refers to general knowledge of the world, social and spelling rules, etc. Procedural memory , the unconscious memory that allows us to remember how to ride a bike or drive a car, is not damaged in the early stages of AD either. If AD patients are recommended not to drive, it is not because they have forgotten how to drive, but rather due to reduced attention and problems finding their way.
The various kinds of memory are affected selectively because they reside in different neural networks and in different brain structures, as shown in table 4 (13.1) (the table needs a careful look as it is fairly complex despite being schematic). Immediate memory depends on the integrity of a frontotemporal circuit and secondary memory (short-term episodic) on the hippocampus (medial area of the temporal lobe) ( figures 6.6
and 6.7
), in the area of the brain where the first Alzheimer’s lesions appear, and thus the first area to be affected.
In brief, the various types of memory are impaired in very different ways in the initial stages of AD, because the first areas of the brain that are clinically affected are the hippocampus and connected areas, while the structures where the other kinds of memory reside remain intact.
First, short-term episodic memory deteriorates; as AD progresses, lesions appear in the cortical multimodal association areas (frontal and temporoparietal; figure 6.5
), which affects semantic memory , and distant memory also begins to be impaired. Procedural memory takes longer to deteriorate as it depends on sub-cortical connections, basal ganglia and the cerebellum, which are lesioned later. Presumably, distant memory resides in all of the cerebral cortex, like semantic memory (abstract memory without specific features) (perhaps the inferomedial part of the temporal lobe is especially important in this). Also, the way in which the different kinds of memory are recorded in the brain is different: short-term memories, which require reinforcement (recall) in order to last longer, reside in the reinforced synapse connections, which are known as synaptic mechanisms mediated by potentiation or synaptic reinforcement; due to this functional mechanism, they are established for a certain time.
Whereas, very probably, distant memory resides in proteins that are created ad hoc by the neurons or in the nuclei of neurons, in DNA conglomerates; in this way memories can last for
58

many years
118,119
. So, memory is a complex matter, and so is its impairment. No wonder – memory is a mental function not only for remembering the past, but also for predicting the future (according to what is known of the past), but that is another matter altogether...
118
Gaffan, 2002 and Vanderwolf, 2007 are examples of authors that consider memory a wider cognitive function than the restrictive concept in everyday medical use.
119
Psychological memory evaluation and its localization (anatomy of the memory) is an immense subject with continuous changes and discoveries, increasing with fMRI use. Bermejo-Pareja et al, 2012 classified memory at the knowledge level of a medical student, and in Bermejo et al, 2008, its psychometric aspects. Matthews BR,
2015, reviews memory dysfunction adapted for neurologists. Squire & Dede, 2015 , review the anatomy of memory. Deep studies on clinical memory manifestations can be found in Kopelman, 2002, and Moscovitch et al, 2005 ; immediate memory in Miller, 1956, and Gobet & Simon, 2000 ; episodic memory is explained in detail in Tulving, 2002 ; autobiographic memory in Urbanowitsch et al, 2013 . The background of neurobiological memory is nicely discussed in Dudai, 1995 ; Alberini et al, 2009, 2014 , and Arshavsky, 2014 , analyse the epigenetic mechanisms of memory storage. Kaku, 2014 (a theoretical physicist) describes the objective of human memory very well. Memory teleology is not only remembering the past, but also predicting the future
(obviously, according to the past).
59

Alzheimer’s disease (AD) usually progresses very slowly. But once dementia has taken hold, it is irreversible and leads to death in a period of time that depends on the age of the patient and how aggressive the disease is
120
. Occasionally there can be periods of stability of some years, rarely longer (periods of stability or “plateaus” have been described of 4-8 years, but this is exceptional). Usually the patient starts to suffer progressive memory loss (episodic memory) and over the course of months or years he experiences gradual cognitive decline
(case 2).
Case 2
Male aged 62 who attended the surgery accompanied by his niece (slightly older than him), one of the few relatives with whom he had always had a good relationship. The psychometric test administered gave a diagnosis of mild cognitive impairment (MCI) of cause unknown and moderate depression (his wife was asking for a divorce). He missed an appointment three months later, but returned on his own (without relatives) the following month. His personal situation was similar and the psychometric tests showed no further cognitive decline. The case was not very clear because it was mixed with a complicated family situation, as he didn’t speak to his wife or children because he ran a busy corner shop, against the wishes of the family. The case was discussed by three physicians: the psychiatry resident thought that it was cognitive disturbance due to depression and anxiety caused by the divorce (he argued that patients with dementia do not see the doctor alone); another thought that it could be the beginnings of Alzheimer’s; and the third maintained the diagnosis of MCI, believing that a longer evolution time was required. And the case took time to develop. At the next check-up,
6 months later, he came with his niece again. He still had the same family problems and the test results were similar again. All the medical examinations, including brain scans were normal. A little over a year later, he returned to the surgery. The niece stated that he seemed the same: maybe a bit more absent-minded, but living his everyday life at a day centre, and very sad because his ex-wife and children took no notice of him, and he had left them the shop for them to run. The cognitive tests had worsened and his memory was clearly worse than in the first tests. He was diagnosed with mild Alzheimer’s and prescribed ACI. In the following years, his very slow progressive cognitive decline continued, and after three years of follow-up, with the diagnosis now confirmed by the progressive evolution, his niece found him a small flat near her home and an Ecuadorean carer to supervise him. Four years later, now with a clinical picture of moderate-severe dementia (needs help for BADL, except eating), the patient died of myocardial infarction.
In brief, a case of AD that was difficult to diagnose initially due to the long and slight cognitive decline, complicated by depression and bad family relationships.
The first mild stage of AD normally lasts between one and six years, and can pass unnoticed.
And it is not unusual for neither the patient nor the family to ask for medical help in that period, as the patient usually plays down his defects and the family blame depression, which often accompanies AD, or “it’s an age thing” when the patient is very old (over 80). MCI
120
See Villarejo et al, 2011 a, with the NEDICES cohort AD mortality data.
60

(mild cognitive impairment) can affect a quarter of those over 80, which predisposes us to think that forgetfulness at this age is due to ageing
121
. The high frequency of auditory deficits in old age do not help either – often the need for names or sentences to be repeated is confused with deafness, rather than attributing it to AD. However, gradually relatives or the patient himself become aware that the forgetfulness is not normal and they visit the doctor.
See tables 5 (14.1), 6 (14.2) and figure 20 (14.1).
The most striking cognitive deficits, apart from forgetfulness, are: temporal orientation (not remembering the day of the week or the month) or spatial orientation (difficulty finding the way in strange places and even getting lost). Little by little, the patient moves into the mild dementia stage. He begins to fail at “instrumental activities of daily living” (IADL), i.e. managing family accounts and money, taking medication, using the phone, taking public transport to unusual places, shopping at the supermarket and other similar things. For the patient, life outside his own home starts to become hazardous and the family notices this, even though he manages well at home, except in complex matters (making a paella or controlling the TV well)
122
.
In the cognitive realm, after the memory disorders come the language disorders (some patients start with these). The patient has difficulty expressing himself and understanding what is being said (dysphasia) and, above all, trouble naming familiar objects or people
(anomia). This, which happens to all of us sometimes, is not pathological if the names are remembered during the day. Vocabulary becomes poorer (verbal fluency). If a normal person is able to name more than 10 animals with four legs in a minute (normally 12 -15), patients with AD do not reach these numbers. They start to have problems reading the newspaper.
Writing deteriorates progressively: first lexis, then syntax, and finally, in severe AD the patient becomes agraphic (unable to write); the signature remains legible until advanced dementia.
121
There are many clinical monographs that described this subtle initial period of dementia ( Signoret & Hawk,
1991; Bermejo & del Ser 1993 ; Parks et al, 1993. Rarely, the subtle memory or cognitive dysfunction, almost stable, could be longer than four years. However, in population-based surveys longer periods are reported (See chap # 22e). In case 2, the very mild and relatively stable initial period persists for 10 years, then the clinical AD appearance begins and then persists for many years, although AD was not his cause of death. Brooks et al, 1993, commented that AD frequently has a “trilinear” evolution, mild at the beginning, sharp decline in the middle, and with final stabilization. For Suh et al, 2004 , only the BADL were curvilinear; other cognitive and functional capacities were linear. In the next chapter, we will describe the MCI concept in extenso .
122
The clinical AD evolution monographs, a part of that referred to in FN # 121, are frequently published in many countries. In Spain, they are by neurologists: Bermejo FP et al, 2004; Peña-Casanova, 2007; Bermejo-
Pareja et al, 2012 . The clinical review data of Knopman et al, 2004 is splendid.
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Figure 20 (14.1).
Evolution over the time of the clock-drawing test in a patient suffering
AD
Evolution of the clock-drawing test in a patient suffering
AD along four years. Mild AD (top); moderate AD
(centre); severe AD (bottom).
Order to design: “Draw a clock with the handles marking the eleven past ten”.
Mild AD: clearly bad, the design is eleven minus ten; moderate AD: missing pointers; severe AD: only difficult sphere. Taken from NCB, Bermejo-Pareja et al, 2012, with permission
The psychometric examination in mild AD reveals various cognitive deficits and impairments in IADL. In the clinical interview, difficultly with abstract reasoning can be tested
(interpretation of sayings). The intelligence tests (WAIS and others) reveal more about the decrease in fluid intelligence ( executive capacities or practical intelligence) than crystallised intelligence (general knowledge, vocabulary). As the disease develops, deficits in certain functions appear: visuospatial, praxic, constructive (drawing) and gnosic. For many families, visuospatial deficits are seen as confirmation of the disease. They see how the patient cannot orient himself in the street or they complain of visual disturbances, which they put down to a need for glasses, but are actually complex visuospatial disorders (detectable with appropriate tests) of spatial interpretation. Another specific disorder is apraxia, the inability to perform complex movements, when there are no motor or sensory problems; constructive apraxia is difficulty in copying or drawing and appears early. See figure 20 (14.1). Apraxias are evident in the intermediate and advanced stages – dressing apraxia is characteristic (inability to put on a jumper or trousers properly). Gnostic impairments (inability to recognise objects by sight or touch) are a disorder of cortical processing. Prosopagnosia , difficulty in recognising the faces of relatives or famous people, is an exponent of this disorder.
As AD is a disease that is initially cortical, of the intellect, in its initial and middle stages emotional capacities are well preserved – the feelings for loved ones (ingrained in the subcortical limbic system ). Perhaps for this reason the patient with AD is often better accepted
62

by the family than patients with other types of dementia (vascular and others)
123
. In the evolution of AD, non-cognitive disorders appear, the most frequent of which is depression
(above all in the first three years), although apathy, lack of interest and passive behaviour are common. Anxiety and irritability usually come later. Catastrophic reactions (excessive emotional reactions to failures at tasks), delusions, false ideas that are resistant to reasoning, hallucinations (unreal visions) and false perceptions (believing relatives to be intruders) are characteristic of the severe stage. Violence and verbal or sexual aggression cause disturbance in the family (often they are motivated by a hostile atmosphere) and lead to isolation.
Disorders of the sleep-wake cycle (nocturnal insomnia, nocturnal wandering (wandering around the house during the night)) are encouraged if the patient is allowed to sleep a lot during the day, eating disorders (bulimia), sexual disorders (hypersexuality – infrequent), sphincter incontinence (need to wear nappies), and episodes of agitation which appear in advanced stages.
In the initial stages of AD, the motor neurological examination is normal, but as the disease advances, anomalies can appear: muscular rigidity, tremors, involuntary muscle contractions
(myoclonus), slowness of movement (can be a side effect of neuroleptics – sedatives that prevent agitation or hallucinations). In the final stages, gait disorders commit the patient to a wheelchair or to bed, and swallowing problems make eating difficult, except for mashed up food. Epileptic seizures and terminal vegetative states can appear, but rarely, as the patients die beforehand.
In short, AD evolves in 5-10 years towards total incapacity and death in patients who are not very elderly, although survival is shorter in community studies (2-7 years)
124
. Its evolution can be faster (months) or slower (survival of over 20 years has been described), but both lengths of survival are exceptional.
123
A population-based study of the dementia proxies in Spain shows the good acceptance of dementia patients by their families, although there is great variability in care taking ( Bermejo et al, 2002, 2004 and Rivera-Navarro et al, 2008).
124
95% of the dementia cases died in this range ( Villarejo et al, 2011 a ) with the data of the NEDICES cohort
(with the Spanish official data of death and cause of death). Survival with dementia in clinical AD patients could be longer (in general, 10 years younger than the community-based dementia patients, when the diagnosis of AD was carried out, because, in general younger and more educated AD cases went to hospitals).
63

Before the epidemic of ageing populations, in the 60s, the decade of the “baby boom”, memory loss in the elderly was classified as either “benign or malignant”, according to whether it remained roughly stable or progressed to dementia (malignant)
125
. Later, other terms appeared for patients who did not have dementia but showed clear cognitive impairments, and these terms multiplied: age-associated cognitive decline; minimal dementia; questionable dementia; cognitive impairment no dementia, among others. But the terminological battle was won by mild cognitive impairment (MCI). All these names, to a greater or lesser extent, allude to a state of “pre-dementia” – an intermediate stage between cognitive normality and dementia. Figure 21 (15.1) shows the stages of evolution of the decline to dementia, although this evolution can stop at the step before dementia, or even reverse, depending on the cause of the MCI.
Figure 21 (15.1).
Stairs type of evolution in the cognitive decline
This scheme shows the cognitive decline in stairs o little by little with multiple ways.
It is frequent the stairs type of decline: first, preclinical or subjective memory loss, then preclinical or subjective loss of several cognitive capacities; or isolate memory loss, or isolate loss of other cognitive capacities; then, MCI (mild cognitive impairment, that is to say objective memory or other cognitive domains loss); and lastly, dementia and several degrees of severity in stairs. The decline could be apparent (black arrows) or unapparent (pointed arrows). Sudden stairs falls are infrequent.
See text FN # 127
125
Kral, 1962, described this entity.
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MCI is a theoretical construct, initially established only for clinical research and drug trials.
The aim was to find a drug that delayed or impeded the appearance of dementia or
Alzheimer’s (AD); later, once its definition had been refined and after over 20 years, it has reached its status of clinical diagnosis, which is used in doctors’ surgeries. MCI has been given various definitions, the latest of which the mental illness classification manual DSM-V calls mild neurocognitive disorder
126
.
MCI presents several features of interest: it is very prevalent – more so than dementia.
Depending on the definition criteria, it can reach a prevalence of 10-20% in over 65s (see figure 22 -15.2). Diagnosing it as early as possible is important because it is often a precursor of dementia and its treatment (or rather preventive measures) would offer the possibility of delaying or avoiding it. At first, it was considered the initial pre-symptomatic stage of
Alzheimer’s (AD) but later it has been seen that it is actually the precursor not only of AD, but also of other types of dementia; also, psychiatric disorders (depression) can cause it.
Furthermore, its evolution is variable: at 3-5 years from diagnosis, the patient might have developed a dementia (5-20%), the MCI might remain stable, or in many cases the patient can return to normality
127
. What is certain is that suffering MCI carries an elevated risk (not very high, but significant) of future dementia and mortality
128
– it is a risky situation but not a stage that leads inevitable to dementia. MCI has been subdivided into categories, of which amnesic MCI has drawn most consensus. It is the type of MCI which most often leads to AD, but is not specific – it can precede other dementias
129
.
126
Bermejo FP, 2002, revised MCI nomenclature at the beginning of the century, its evolution is not uniform, could progress, be stable or came back to normal cognition, Bermejo-Pareja et al, 2016 a.
127
Ronald Petersen was the forerunner of MCI. This innovative neurologist from the Mayo Clinic (Rochester,
Minnesota, USA) worked in one the best Neurology Dpt. in the world. Mayo Clinic boasts, because is true, the oldest and best system of huge mechanized archiving of clinical histories in the world. This system transports the medical histories from the clinical board to its store and over the period of a century, only three medical reports are missing. Exceptional. Petersen, 1995, 2003, 2011, 2014 has maintained this nomenclature, which is used by most neurologists and recommended by the AAN. The definition of MCI has international consensus ( Winblad et al, 2004 ). The recent DSM-V ( American Psychiatric Association, 2013) rechristens this entity as mild neurocognitive disorder. However, many clinicians maintain that this entity is an artificial construct, not a real clinical entity.
128
See the NEDICES cohort data ( Contador et al, 2014; Bermejo-Pareja et al, 2016 a). Winblad et al, 2004, and
Petersen et al, 2014, underline the multiple MCI aetiology: AD-type (the most frequent), vascular, stress, psychiatric disorders (depression and others) and others. Bermejo et al, 1999, 2002, 2016, review this subject.
129
See Bermejo-Pareja et al, 2016 b. The ACI drugs generally admitted: tacrine (not used because of adverse side effects), donepezil, rivastigmine and galantamine, determine a mild symptomatic improvement in many AD patients (not in all) for a limited time (6 months-2 years). All these drugs and many others have been trialled in
MCI to delay AD onset without success ( Williams et al, 2010; Bermejo-Pareja et al, 2016 a; Kane et al , 2017).
65

Figure 22 (15.2).
Prevalence of cognitive states in the baseline of NEDICES cohort
Main cognitive alteration in the elderly in NEDICES (rounded figures). Dementia plus doubtful would be 7% ; MCI around 10% , and around another 10% very mild memory deficit or subjective memory loss; around 73% were cognitively “normal”. Taken from Bermejo, 2002
So, MCI was put forward originally in order to test drugs that would detain or delay AD, but none of the drugs that have been trialled has succeeded in this, even those that improve AD patients, which are ACI and memantine. Also, in MCI, treatments that impede the accumulation of
$ ȕ DQWL
beta amyloid drugs) are being tried, without success for the moment
130
. Various authors have considered it more interesting to try to treat patients who are not at the prodromal stage (the clinical onset of memory loss or MCI), but rather before any clinical symptoms of AD appear. This stage is what has been called: preclinical or pre-symptomatic
AD. Some authors differentiate between the pre-symptomatic and preclinical stages
131
. In the former, there would only be the pathological disturbances typical of AD: neurofibrillary degeneration (NFD) and senile plaques (SP), which are detectable by their manifestations in the cerebrospinal fluid (CSF) or by neuroimaging, but no clinical impairment (not even in psychometric tests); whereas in the preclinical stage there could be some subjective memory impairment. The dividing line between this and MCI would be difficult to draw, as it has to be taken into account that if clear memory impairments appear, the patient could be considered as suffering from MCI. To understand these differences better, review figure 3 (5.1).
130
Scinto & Daffner, 2001, review this subject. Optimistic analysis about it can be found in Dubois et al, 2007, and Sperling et al, 2011. Also, more critical analysis in Khachaturian et al, 2016. In reality, there is not consensus on this subject.
131
Anand et al, 2014, performed a wide and documented analysis of pharmacological AD therapy. More data in chap # 18.
66

“And how would this pre-symptomatic or preclinical AD be diagnosed?” Well, this is another theoretical construct that the advance of medical science has established. The diagnosis would be attributed to individuals who were practically normal from the cognitive point of view, but
KDGVRSKLVWLFDWHGPDUNHUVRI$'UHGXFWLRQRI$ ȕ DQGDQLQFUHDVHLQWDXLQWKH&6)VHOHFWLYH atrophies in the region of the hippocampus, detectable by CT, MRI or SPECT and an increase
LQWKHFDSWXUHRI$ ȕ LQ3(77KHREMHFWLYHRIHVWDEOLVKLQJWKLVGLDJQRVWLFODEHOZKLFKKDVDOVR been called Alzheimer’s without dementia , would be the trial of drugs designed to avoid AD manifesting itself clinically. These clinical trials are difficult to implement because the biomarkers that can be detected in the organism and that warn of the risk of sAD have little predictive capacity, and for ethical reasons (a drug would have to obtained that avoided sAD and had no adverse side effects so that everyone with Alzheimer’s without dementia could take it without any fear). The trial with herbal extracts (ginkgo biloba) has not been successful
131
.
67

Well, the prophets of doom are no less than Alzheimer Disease International (ADI), the WHO and many global scientific authorities, which, besides, use fairly solid calculations
132
. See figure 23 (16.1), which is highly simplified.
Figure 23 (16.1).
Dementia prevalence increase and countries (by socioeconomic development)
Observe that in the developed countries (light grey) the dementia prevalence scarcely increase over the time. The increase in the low and medium rent countries is enormous (dark grey). The scheme it is not performed with the last decade data that pointed out a decrease in the dementia incidence in developed countries. From ADI, 2009, with permission.
We’re going to give the international authorities as hard a time as possible: nearly all the statistics presented are based on data on the increasing of ageing and on the prevalence and incidence of dementia and Alzheimer’s disease (AD) from a decade ago. It is known that the main risk factor (RF) of dementia and AD is ageing, and this is very relevant in the world because of the considerable increase in survival. If the data are based on stable prevalence and incidence of dementia and increasing worldwide ageing, the increase in cases of dementia and
AD will be extraordinary. See figure 23 (16.1). Judging by these data, the prevalence of dementia and AD could have quadrupled by 2050. So the WHO has forecasted that: “the number of people with dementia will almost double every 20 years, with the majority of the increase occurring in middle-income countries in rapid development”. Currently, 58% of
132
Brookmeyer et al , 2000, 2007 , the Alzheimer’s Association, 2015 for USA , and Alzheimer Disease international (ADI), 2009, 2015, for the whole world, alert us to the future increase of dementias. The
Alzheimer’s Association maintains that AD is the fifth cause of elderly mortality in USA. However, cardiac failure, stroke and prostate cancer have decreased in the last years in USA, and AD mortality has increased 71% in the same period. Probably, the evaluation of the recent increase of AD as a cause of death, which was traditionally underestimated it, could be due in part to better recognition of AD as a cause of death ( Ganguli &
Rodriguez, 1999 ; Romero et al, 2014 ).
68

people with dementia live in under-developed countries and this proportion is projected to rise to 71% by 2050
133
.
But what if the calculations weren’t as accurate as the authorities claim? And what if, as has happened with tuberculosis and cholera
134
, AD were to decrease due to the same improvement in health which has led to the increase in human survival? The aforementioned calculations have not taken into account a fact that has been emerging in the last decade: the decrease in the incidence of dementias and the plateauing of its prevalence in high-income countries
135
. See table 7 (16.1).
133
WHO, 2012, have forecast the doubling of dementia cases every 20 years, maintaining that the highest increase will be found in less developed countries. The Asian and Chinese data are a cause for worry ( Wu YT et al, 2015 ). In addition, in Spain there are projections about the future burden of dementia ( Soto-Gordoa et al,
2015 ) and studies on the future cost of the dementia increase ( Boada et al, 1999; and Coduras et al, 2010 ). Not all these data take into consideration the new fact of the decline of dementia incidence and prevalence in the developed countries. See table 7 (16.1).
134
135
See Bermejo-Pareja et al, 2016 b for a wider explanation
See Jones & Green, 2016. The authors cited in table 7 (16.1) include the main studies that have been performed. This table does not the findings of Akushevich et al, 2012, (a very complex survey) that show the recent decline of AD in USA, or the survey of Sposato et al 2015, in Ontario (Canada) because it is a preliminary survey. The comparative survey of Pérès et al 2017 is not included in the table due to its complexity .
69

Table 5 (16.1). Main cohorts with decreasing elderly dementia/AD (over time)
Survey abbreviation
Author/year
Country Period Survey type*
(Decrease )
LTCS USA
ZARADEMP Spain
HRS USA
1982-2004 Prv/Mixed Dem
1993-2002 Prv/Dem
Varios USA y. Prv-Inc/Dem/AD/ MCI
Rotterdam Study Holland 10
KP Sweden 4-7 y.
CFAS UK
Two census cohorts Denmark
Inc/Dem
Framingham Heart Study USA Inc/Dem
CFAS UK
Einstein Aging Study USA Inc/Dem
Pathological survey
Amyloid burden pathology Switzerland 1972-2006 Decrease amyloid +
Kövari/2014
*Study type: Prv: Prevalence: Inc: incidence; Dem: Dementia
Abbreviations; y: years; +: statistically significant; +/- not statistically significant
Acronyms:
LTCS : Long Term Care Study: HRS : Health and Retirement Study;
ZARADEMP : Proyecto de demencia en Zaragoza;
KP : Kungsholmen Project;
CFAS: Cognitive Function and Ageing Study; +:
Completed references in Bibliography section; see FN # 135 .
There is an historic fact that lends plausibility to this hypothesis: the decrease in incidence of ischemic heart disease (myocardial infarction) that happened in the latter half of the 20 th century and how it was approached by official science (it’s easy to be wise after the event, of course). As Jones and Green describe in a recent editorial, the administrative authorities in the
US took more than 10 years to acknowledge that the incidence and mortality from myocardial
70

infarction had clearly declined since 1964. The decrease was demonstrated that year in a study in California but was not officially recognised until 1974
136
. In other words, it is not necessary to resort to events at the beginning of the 20 th
century – we have a closer example. Not even
50 years have passed since something similar happened with myocardial infarction.
But let’s be realistic: it seems that the prevalence has stabilised in the developed countries and it is even very likely that the incidence is decreasing ( table 7 (16.1) again). It is more unlikely
(not very plausible) that this situation will be repeated in poor and developing countries. And as ageing is a global reality we must acknowledge that it is likely that the depressing predictions of ADI and other official organisms will come true, in part. However, four decades is a long time, and we should be somewhat optimistic (science advances exponentially and new therapies or drugs might appear, above all modifying epigenetic factors – a largely unexplored manipulation). In more than 30 years, many things could happen in the realm of dementia and AD
137
. The preventive measures to reduce tobacco use, focused on the prevention of CVD, respiratory diseases, and lung cancer are going to have an effect on the prevention of dementia and sAD. And the control of other RF and the expansion of general education are going to improve health. All this could brighten the bleak outlook, which has been presented as almost certain fact
138
. We should be cautiously optimistic. The past helps to predict the future and the incidence of many diseases decreased before the arrival of curative drugs. It is plausible that the same could happen with AD in the future.
136
Review Jones & Green, 2013 .
137
For example, the therapies that decrease any associated risk factor of AD such as ageing ( Blasco & Salomone,
2016 ). They will be possibilities to treat epigenetic factors (Chap # 11), a strategy that has not yet been accomplished well.
138
Many authors, mainly geriatricians, have insisted on the importance of RF prevention of the chronic diseases as a strategy for delaying aging ( Darnton-Hill, 2004; Ribera Casado, 2014 ; Blasco & Salomone, 2016 ), and many other scientists have had the same idea ( Gluckman et al, 2017 ).
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The answer is clear: none. It surprises many people, but this is the reality. The doctor
(preferably the expert – geriatrician, psychiatrist, or above all the neurologist in Spain) does not need any complementary tests in order to make a diagnosis of Alzheimer’s disease (AD) with high probability (generally over 80%)
139
. In AD diagnostic accuracy ranges from 63-
90%, although the probable AD criteria (NINCDS-ADRA) can slightly exceed 90% in university hospital studies. The diagnostic accuracy of the expert is greater than any of the new techniques, including biomarkers in cerebrospinal fluid (CSF) and neuroimaging
140
.
Some will ask: “So what does the expert do to diagnose so easily?” Simply, he detects a history of slowly progressive memory loss and the loss of functional capacities (IADL)
(progressive), which impede the adaptation to work, social or domestic life, the neurological examination being consistent with the diagnosis (absence of motor impairments). In any case, normally, in order to increase this high probability to over 90%, various complementary tests are performed, to exclude other possibilities such as vascular dementia (VaD) or other highly improbable ones (tumour in the temporal or frontal lobe, hydrocephalus, and others). So the diagnosis of AD is a diagnosis of exclusion. Also, it is necessary to reassure the family, who often think the patient has “something bad” in his head (a tumour). Obviously, in a percentage of cases (around 20%) the history (or neurological examination) is more complex and requires a more detailed evaluation, because there are other kinds of relatively infrequent NDD, VaD, or psychiatric or systemic (B
12
deficit) disorders, which can bring the diagnosis into doubt, and require precise investigation
141
.
139
The diagnosis of neurological diseases (and AD in particular) is achieved in 80-85% of cases by clinical history, 10-15% by examination and only in 5-10% by complementary data: biochemical evaluation, neuroimaging and so on ( Chimowitz et al, 1990; Whitehouse & George, 2008 ; pp: 216).
140
The AD diagnostic criteria most used are the NINCDS-ADRDA, McKhann et al, 1984, (revised by McKhann et al, 2011 ); However, there are others (DSM-IV and V, ICD-10), all with different diagnostic efficacy
( Erkinjuntti, et al, 1997 ). All of them are probabilistic criteria . There are no clinical, biological or neuroimaging data that permit a certain diagnosis of AD, not even the pathological brain exam. The possibility of diagnostic success with the McKhann et al, 1984, criteria was validated versus the pathological gold standard ( Mendez et al, 1992 ; Nagy et al, 1998 ) it has high sensitivity (80-90%) and low specificity (little more than 50%). (There are investigations with poorer diagnostic results, e.g., Brunnström & Englund, 2009, from the Lund U in
Sweden). The recent criteria of McKhann et al, 2011, are awaiting validation. The new neuroimaging exam (MRI
ZLWK YROXPHWULF KLSSRFDPSXV HYDOXDWLRQ 3(7 DQG WKH &6) $ ȕ DQG WDX PHDVXUHPHQWV LQFUHDVH FOLQLFDO diagnostic accuracy, but it is not clear to what extent. The latest systematic review of CSF determinations
( Ritchie C et al, 2017 ) in predicting the MCI progression to dementia has fairly bad results (sensitivity: 75% -CI
95%: 67-85-; specificity: 48%-88%). However, there are other more optimistic opinions ( Huynh & Mohan,
2017). The ADNI research ( Weiner et al, 20013, 2017 ), designed to have better accuracy in AD diagnosis has a conclusion: no isolated measurement: psychometric, CSF, or neuroimaging is a better predictor of AD dementia than the combination of multiple indicators. Possibly, the best combination is clinical, cognitive test and MRI data ( Gomar et al, 2014 ).
141
There are more than 100 causes of dementia ( Wells, 1977; Bermejo & del Ser, 1993 ), although the vast majority are AD, VaD and NDD (PD, FTD, LBD and so on), and a minority of infrequent dementing disorders, few of them treatable ( Wahlund et al, 2002) . For this reason, AD diagnosis is a parsimonious study excluding other dementia possibilities (B
12
deficit, hypothyroidism, CNS tumours, hydrocephalus and so on). The diagnosis of any dementia might be maintained with some structural neuroimaging ( Knopman et al, 2004 ). CT is the routine neuroimaging exam ( Díaz-Guzmán et al, 2002; NICE, 2007 ). MRI is used increasingly in affluent
FRXQWULHV 7KH &6) GHWHUPLQDWLRQ RI $ ȕ DQG WDX KDV OLPLWDWLRQV DV URXWLQH SUDFWLFH
Noel-Storr et al, 2013,
Ritchie et al, 2017) . MRI with volumetric measurement (temporal lobe, hippocampus), fMRI, PET and others are techniques for very specialized Centres and there are many regulations for their use ( Apostolava, 2016 ). The new markers of AD ( Murray AD, 2016 ) are waiting for validation.
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“And why is the diagnosis of Alzheimer’s so simple that a doctor or neurologist can do it with no more than a clinical examination?” Well, so simple and so complicated. It is simple because there are many people with this disease among the very elderly; most people know one or several. When an elderly person has lost memory, starts to mix people up, not remember relatives or birthdays and, above all, have difficulties managing household accounts or orienting himself in a place he does not know, the family interprets this as the person having the beginnings of senile dementia; at this point they see the doctor, who usually confirms it. A simple psychometric examination done with pencil and paper is sufficient: a
Mini-mental (MMSE) and the clock-drawing test (see figure 20 -14.1) are usually enough at the middle or advanced stage of the disease. At the early stages (mild dementia) the diagnosis is more complex and as well as a detailed clinical study, it is necessary to perform a neuropsychological examination (usually done by psychologists) or complementary tests
(analysis, brain scan).
It is true, as we have said, that in a small percentage of cases of infrequent NDD, such as frontotemporal dementia (FTD), previously Pick’s disease, Lewy body dementia (LBD), associated with Parkinsonisms, and other rarer NDD, can complicate the diagnosis. More infrequently, psychiatric problems such as intense depression ( depressive pseudo-dementia ) and some other psychiatric disorders can cause diagnostic difficulties (although psychiatric patients normally have a previous history of these disorders). But this also happens. And when it does, neuroimaging and pathological tests are not a magic wand that can be waved to give an accurate diagnosis. If you don’t believe it, read case three, with a brain biopsy and everything.
Case 3
Male aged 68 who was admitted to A&E with a clinical picture of convulsions, high fever and coma. The neurological examination showed light coma (he could be woken but fell unconscious immediately) and great generalised stiffness. Brain abscess and meningitis were ruled out by a brain scan and CSF analysis. A nephew and neighbour said that he lived alone: his wife had died two years previously and his two daughters lived in another city. The neighbour stated that he had seen him the month before and had looked unkempt and forgetful, and he knew that the doctor had diagnosed him with depression and that he took medications. This was confirmed by blood and urine samples days later; he was taking an antidepressant and a neuroleptic (anti-psychotic drug). He was diagnosed with neuroleptic malignant syndrome, an adverse reaction to the neuroleptic drugs and he was admitted to a neurology ward to be treated. After a week of treatment his level of consciousness improved but he remained drowsy, inattentive, depressed, enable to care oneself (BADL). He still had labile hypertension; he refused to eat and wanted to escape from the hospital in his pyjamas.
The diagnosis of dementia also needs an objective psychometric exam. The most used is MMSE ( Minimental
State Examination ), a very well established psychometric test ( Folstein et al, 1975 ), which can be performed with only pencil and paper. MMSE quantifies cognitive performance by means of very simple questions about temporal (current day, month, year), personal and spatial data and the meaning of sample questions and designs.
There are many English ( Tombaugh & McIntyre, 1993 ) and Spanish adaptations ( Bermejo FP et al, 2008 ) of
Foltein’s original test. The MMSE-37 used in NEDICES cohort is adjusted to low level education people and has
37 points ( Prieto et al, 2012 ). More simple cognitive tests are used in community health surveys ( Zunzunegui et al, 2002 ). Sometimes dementia evaluation requires an extensive psychometric battery ( Strauss et al, 2006;
Bermejo et al, 2008 ).
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A daughter came quickly to see him, but could not stay with him due to her job, and hired a carer to look after him during the day. His health was fragile, he was apathetic, and suffered delusions and occasional hallucinations so it was suggested that his previous depression could have been caused by an organic disease of the nervous system (Alzheimer’s or another dementia). After performing all kinds of analyses and brain scans, which did not clarify the diagnosis, and given his scarce improvement over nearly a month, the medical team came to the conclusion that in order to rule out a possible brain disease (AD, organic dementia – there are numerous very rare NDD – or even an infectious disease such as Whipple disease) a brain biopsy had to be performed, and with the family’s consent, he was tested. The histological examination of the brain showed some senile plaques (SP) and neurofibrillary threads (NFD); the pathologist declared that the findings allowed a diagnosis of possible Alzheimer’s, of mild intensity. With this diagnosis he was sent to a hospital for chronic patients and the hospital history was left like that, but the case did not finish like that.
Seven months later, a smartly dressed man arrived in the neurology ward, with flowers and a box of chocolates. He was happy. Neither the nurses nor his neurologist recognised him.
When he told them his name and thanked them for the care he had received, the staff were astonished. He said that he lived at home, led a normal life with his carer, and that they were planning to get married. With this happy ending, the retrospective diagnosis of the case was: remitted severe depression and cured neuroleptic malignant syndrome. Logically, the findings of the brain biopsy did not correspond to Alzheimer’s dementia. It is known that many elderly people have Alzheimer’s-type lesions but do not suffer from the disease. When he recovered from the adverse effects of the medicine and his depression, the patient started a normal life, helped by his carer. A happy ending for the patient and a surprising ending for medicine.
The case
142
shows that when there is not a well-founded clinical diagnosis (the case was clinically dubious in many aspects, as the patient lived alone), the medical tests (including the brain biopsy) are not, many times, able in themselves to clarify the diagnosis of Alzheimer’s.
This diagnosis is always a diagnosis of probability and exclusion of other causes. Thus there is nothing surer than a specialist with experience and a patient with a clear history in order to reach a reliable diagnosis. A clinical history and a neurological and basic cognitive examination identifies 80-90% of the cases of sporadic Alzheimer’s (sAD), without requiring any other analysis or complementary test, although a CT or RMI is usually performed (in order to rule out unlikely brain tumours, subdural haematoma, and vascular brain lesions), as well as biochemical blood analysis, to confirm that the patient does not suffer from any systemic disease (severe hepatopathy, vitamin B
12
deficiency or other diseases that can cause cognitive deterioration). The most difficult cases to diagnose are those that involve patients with severe sensory defects (deafness, blindness), or very old or frail patients, such as those over 90 whose social activity is usually very limited. It must be taken into account that the definitions of dementia are largely sociological (cognitive deterioration of sufficient intensity
142
This case is peculiar in many aspects. First, the clinical history was poor (the patient was isolated); the patient saw several doctors (private, public), but irregularly. He had a diagnosis of depression but the medication
(several drugs) intake was presumably irregular. Second, malignant neuroleptic syndrome is a very infrequent adverse side effect of neuroleptics ( Dobbs et al, 2009 ; pp: 42-43 ). Third, to practice a cerebral biopsy in a dementia case is very unusual, although it is performed to detect possible treatable dementias or in rapidly progressive or doubtful cases ( Warren et al, 2005; Bermejo-Pareja et al , 2012; pp: 259, 525). False positive cases in a pathological diagnosis of AD are possible (its specificity is not high).
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to cause social or domestic incapacity) and that very old people have very few domestic tasks
(above all men) or social activity (disappearance of friends and close relatives of the same age). Infrequently, an evaluation by an expert in dementias, who are usually found in the large hospitals of the country, is required. Sadly, there is only a very low percentage of dementia cases (less than 5% and perhaps only 1%) that have treatable or curable causes (vitamin B
12 deficiency, intense hypothyroidism, severe depression and others), which must always be ruled out. In the community, the vast majority are caused by sAD or vascular dementia
(VaD), which are generally associated. Severe senile Parkinson’s is the entity that is most often confused with Alzheimer’s.
As we have seen with the example of this patient, it is worth pointing out that the pathological criteria of Alzheimer’s are also probabilistic , despite having been well analysed for decades
(chapter 8) and the fact that its characteristic lesions have been described perfectly. But the practical implementation of these criteria has its difficulties, and traditionally, the diagnostic concordance between pathologists has been fairly limited due to the absence of gold standard diagnostic criteria or criteria of pathological diagnostic certainty
143
. It should also be pointed out that population-based pathological studies (not in hospitals) have shown that sAD is not a well delimited entity in the very old. Many times AD-type lesions are mixed with vascular lesions and other pathologies (especially from the age of 90, where AD-type lesions are less prevalent), which is why the current term of dementia-Alzheimer’s syndrome has appeared
144
.
(A step backwards historically as in the 70s the diagnosis of senile dementia was changed to
Alzheimer’s)
145
.
143
The diagnostic concordance in dementia diagnosis among pathologists was only moderate in the past ( Chui et al, 1993) . With immune-histological techniques the agreement seems to be better; nevertheless, the consortium
BrainNet Europ e, stated that the concordance is only good when the NFD is extensive in the brain ( Alafuzoff et al, 2008, 2012 ), and the agreement in VaD is poorest ( Alafuzoff et al, 2012 ). The new criteria of the NIA-AA seem to have better agreement ( Montine et al, 2016 ).
144
For the readers interested in this subject we recommend Neuropathology Group …, 2001; Zaccai et al, 2006 ;
Yankner et al, 2008; Matthews et al, 2009 ; Schneider JA et al 2007, 2009; Attems & Jellinger, 2013. There is a high frequency (70-80%) of mixed pathological lesions in old dementia patients. For this reason, Richards &
Brayne, 2010 , and Khachaturian & Khachaturian, 2015 advocate the term AD-dementia syndrome. In addition , in very old dementia cases the pathological data are very complex (Zaccai et al, 2006; Jellinger & Attems, 2010;
Attems & Jellinger, 2013;Matthews et al, 2013) ; and in many old-old cases, the pathological diagnosis is missing because there is no clear cause of dementia ( Boyle et al, 2013). Crystal et al, 2000 series have missing pathological diagnosis in around 50% of nonagenarians.
The idea that sAD is a heterogeneous disorder has increasing evidence from many sources: many pathological subtypes (Murray et al 2011); diverse physiopathologic mechanisms (reviewed in Lock, 2013 ; pp: 154-55 ; Lista et al, 2016 ; Hunter & Brayne, 2018 ), and, obviously, from genetics ( Wingo et al, 2012 ). Nevertheless, some authors postulate the uniqueness of sAD ( Nelson et al, 2011, 2012; Hyman et al 2012).
145
See chapter # 18.
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Alzheimer’s disease (AD) has been described in lay terms as accelerated ageing or as a hereditary disease; both descriptions have been rejected by medicine and by the media.
However, they have persisted because they are old beliefs. Well no, Alzheimer’s isn’t exaggerated ageing, according to most authors
146
, and nor is it a hereditary disease (barring the 0.5-1% of familial AD cases): in sporadic AD (99%), heredity has the same importance as in other diseases like diabetes, obesity and high blood pressure (chapter 4).
But, of course, there is some truth in the popular concepts. The main risk factor (RF) of AD is ageing. AD is exceptional below the age of 50, infrequent between 50 and 65, and from this age the frequency increases to 1-2 cases per hundred from 65 to 70, about 10 in the period from 75-80, and continues to increase until about a third of those in their 90s have the disease, and nearly half of those over 100
147
. It can be said that normal ageing does not imply clinical cognitive loss, or even better, in the healthy elderly person, some intellectual capacities improve. The knowledge of the world and the way life is, and wisdom about life and professional matters, which accumulate over the years, increase and become clearer with age.
This is what is known as crystallised intelligence , which in primitive societies belonged to the venerated elders due to their wisdom. It is true that some cognitive capacities decline with age: reaction speed, memory and others (this decline starts from youth or adulthood), but they remain within the limits of normality, and can only be detected with psychometric tests
(reaction times, complex examinations). That is to say, sAD is frequent in old age, and very frequent in over 85s, but is considered as something abnormal. Ageing can run its course
146
There is not unanimous agreement. The neurologist and investigator, Peter Whitehouse, and his colleague
Daniel George, 2008, maintain that sAD is a sickness entwined with aging, and not a very well defined nosological entity. This thesis could be heterodox in same way, but has much evidence in its favour.
Historically, the change of senile dementia to AD was in the 70s and the historian, J Ballenger, 2008 , in his book and blog (https://conquerconfusion.wordpress.com/tag/history-of-alzheimers/) commented that this change was for two reasons. First, the anguish about ageing in a society such as the US that preferred its medicalization.
Second, the assimilation of this change by important medical societies and the NIA that prioritize research in the new field. George et al, 2016 , wrote the new idea: “cognitive frailty was the result of a single disease-process called “Alzheimer's” that existed outside the spectrum of normal age-related changes and could be specifically attacked”. This position was interesting for investigators, as Katzman commented ( see previous blog ): “there was money for research in Alzheimer not in ageing”. Several epidemiologic authors maintain the ageing view
( Brayne & Calloway, 1988; Hupper et al, 1994; Launer et al, 1999; Richards & Brayne, 2010; Hunter et al,
2013 ). For them there could be a continuum between normal ageing, cognitive decline, senile dementia and AD, and in this continuum, ageing is primordial (recently, Aisen et al, 2017 from a clinical arena and Ferrer, 2012 , in its pathological underpinnings maintains this opinion). Also from the biological field, Mesulam, 1999 , considers that the ageing would accelerate neuroplasticity dysfunction that makes AD more likely, and others ( Swerdlow,
2007 ; Yankner et al, 2009; Boccardi et al, 2017 ) considered that ageing has a definite role in AD. For other authors ageing is only an RF. Some authors consider aging as only a time proxy of life: Peto et al, 1985; Peto &
Doll, 1997. Prestigious pathologists and authors from the scientific establishment ( Nelson et al, 2011; Hyman et al 2012 ) consider AD as a unique entity, in their opinion progeria is a disease that produces accelerated ageing and is not associated with AD. However, others have indicated that exceptional family longevity protect against
AD and MCI ( Lipton et al, 2010 ; Consentino et al, 2013 ). We need a better understanding of ageing…
147
Olshansky & Ault, 1986, make explicit the change of the preponderant disorders in the developed countries from infectious diseases to vascular and then to chronic disorders. For these disorders that are complex (many genes and environmental causes), many authors and WHO prefer the term of non-communicable diseases
(NCD): CVD, DM2, obesity, HBP, cancer, osteoporosis, including AD and others, which, in general, increase with ageing ( Lango & Weedon, 2008 ; Petronis, 2010 ; Barouki et al, 2012, Panoutsopoulou et al, 2013; Faa et al, 2014) .
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without cognitive deterioration and some cognitive capacities can even improve; this is called
“healthy or successful ageing” and “positive” ageing exists
148
.
Other terms that form the title of this section are not as well defined, as you could imagine.
And now, a little aside for the “non-doctors” who may not be used to the relative imprecision of medical definitions, which are not as accurate as formulas in maths or physics. Health and illness are not that easy to define, and even the WHO definition of health includes “wellness”, which has psychological and sociological, rather than biomedical connotations
147, 149
.
Moreover, in many chronic illnesses that have a slow evolution, (such as sAD), it is often difficult to determine their beginning. The terms in the title must be considered with this qualification. Alzheimer’s is a chronic disease (that lasts more than 2 or 12 months, depending on the criteria), it is a complex disease, and is one of the non communicable diseases (NCD), a term often used by the WHO. These categories are not exclusive, and like all words, have a birth and usage
149
. The WHO uses the term NCD a lot because these are the diseases that are growing the most in the developed world, as opposed to communicable diseases (infectious and contagious)
147
. But also, sAD is a neurodegenerative disease.
“What are complex diseases ?” Many texts and dictionaries do not define them, but the concept is interesting. They are ailments that involve multiple causal factors: genetic (multiple genes) and epigenetic, gene-environment interaction, and other clearly environmental factors
(stress, physical inactivity, inadequate diet, toxic habits). It is likely that the interaction of all of these begins in the womb, takes shape in infancy and is consolidated over many years
(chronic diseases in their evolution). “But why complex?” The name derives from the fact that monogenetic diseases are considered “simple”, as they are caused by a single gene; diseases involving many genes are considered “complex”
150
, so sAD is a complex disease – around 20 genes are involved.
“But don’t they say that AD is a neurodegenerative disease?” Yes, it’s that too.
Neurodegenerative diseases (NDD) are conceptualised as a group of progressive disorders of the NS that lead to death, generally, over many years, and involve neuron loss through apoptosis (the neurons slowly decay and their remains are absorbed without inflammatory alarm). Apart from amyotrophic lateral sclerosis (ALS), which has rapid evolution, the rest are chronic like Alzheimer’s and Parkinson’s (PD), FDT, LBD and others. Some of these
148
The subject of cognitive performance throughout life is exciting. Deary et al, 2004, analyse this subject, commenting that from 11 to 80 years, psychometric intelligence persists in a high percentage of people. Not all cognition capacities persist. Reaction speed decreases from the 20s, and some general aspects from the 40s
( Singh-Manoux et al, 2012). In the elderly, as many other capacities, cognition is variable and complex ( Birren et al, 1992 ; Craik & Bialystok, 2006; Erber, 2013 ). Harada et al, 2013, indicate that in the normal elderly the main cognitive changes are a decrease in processing speed, some aspects of memory, language, visuospatial and executive functions; changes are minimal or small and should not result in impairment in function. The majority of elderly people will develop neither dementia nor MCI. Walhovd, et al, 2014, indicate that the decrease in elderly cognition is a continuum from normality to dementia; there is not a categorical distribution. Positive views: “successful aging” ( Rowe & Kahn, 1987 ; and Chap # 23): elderly people with good health and cognitive preservation; “positive aging”: in which the elderly would lead a proactive and happy life, independent of their health ( Erber, 2013 ; pp: 391-2) See FN # 266.
149
Words, like all live beings, have a birth and death. The median life of words in Spanish is 40 years. Some words change their meaning to survive. Some medical words like “illness” have changed their meaning in the last decades and they are not the same for all medical professionals ( Alonso, 2004 ).
150
See Bertram et al, 2004, 2010; Mayeux, 2003, 2005.
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NDD are genetically, clinically and pathologically interrelated
151
and the precise cause is unknown, but in these diseases deposits of proteins that have acquired an anomalous formation are produced, and they form intra- or extra-cellular accumulations over long periods of time, such as
$ ȕ LQV$'DQG synuclein in PD. It has been discovered recently that these misfolded proteins can (in AD and PD) multiply and be transmitted between neurons via the synapses, as happens in mad cow disease or Creutzfeldt-Jakob disease in humans ( prion diseases ). This is probably only a multiplication (or transmission) mechanism of intracerebral anomalous proteins, since it is has not been found to be communicable between humans, as occurs in prion diseases. Nevertheless, the jury is out on this matter as there are authors who maintain that AD and PD are diseases with prionic physiopathology
152
.
To summarise, sAD is a chronic, complex (polygenetic with environmental factors that influence its genesis) disease, which manifests itself molecularly as a deposition of misfolded proteins -
$ ȕ LQ WKH VHQLOH SODTXHV DQG WDX LQ 1)'
– and other pathologies (neuronal and synaptic loss) and biochemical events. Also, it is a neurodegenerative and non-communicable disease. “That’s a lot of things in order to not know exactly what it is” commented a wellinformed relative to whom I had tried to explain what each thing was for a long 20 minutes. In the end I gave in and admitted he was right. But I said, somewhat mysteriously, “We have the same understanding of AD as we do of cancer, more or less.” And my interlocutor quickly objected, “Yes, but some cancers are cured with medicine and radiotherapy – not
Alzheimer’s”. Again, obviously, I had to admit he was right.
It is worth mentioning something about Alzheimer’s that does not appear in the press (one of the advantages of reading this monograph). Alzheimer’s is a systemic disease i.e. it manifests itself in the whole body (there are blood alterations: leukocytes, platelets, inflammatory and immunological proteins) although its pathological and clinical manifestations only appear in the brain
153
. The intention here is not to discuss the hypotheses about what Alzheimer’s is, but we should not leave out the fact that some authors maintain that it is a disease of vascular origin, or that its cause lies in cellular biochemistry (excess of cellular oxidation which
151
The concept of NDD is described in Calne, 1994; Mayeux, 2003, 2005; Jellinger, 2008; Bermejo-Pareja,
2011, a, b; Sutherland et al, 2013 and its interrelationships that occur in AD-type dementia ( Nelson et al, 2016 ), in non-AD NDD ( Kertesz & Munoz, 1998 ) and in other more controversy entities ( Jack et al, 2016 ). An interesting view of AD neurodegeneration is from, Ferrer, 2012, that considers AD neuropathology and dementia to be as similar as arteriosclerosis in CVD and stroke that could be asymptomatic or symptomatic .
152
The Nobel Laureate, Stanley B Prusiner, 2013, was one of the first to comment that some NDD could be assimilated to prion pathology. Prusiner was invited to the SEN Valence Congress (1990) and in private conversation he complains of the scarce attention to his hypothesis in the academic milieu – he even gave the example of a lecture with only one listener… in the Spanish meeting the audience was large, even though he was not yet Nobel Laureate. Several authors ( Hardy & Revesz, 2012; Goedert, 2015 ) have commented on this
K\SRWKHVLV:DONHU -XFNHUSURSRVHWKDW$ ȕ WDXDQGRWKHUEDGO\IROGHGSURWHLQVGHSRVLWHGLQ1''PXVW be called “proteinaceous nucleating particles” to highlight the molecular action of the agents and to avoid the term “prion” provided that its infective capacity is not demonstrated in the NDD (AD included). We must await the end of the story…
153
See Scott, 1993 ; Morris et al, 2014, about AD extraneuronal aspects; Zhang et al, 2013 analyse the immunological dysfunctions; Krstic & Knuesel, 2013, discussed chronic inflammation in AD, and Swerdlow et al, 2014 and Boccardi et al, 2017 discuss mitochondrial dysfunction as a possible cause of AD. Vascular alterations as causal factors in AD is discussed in FN # 159 and 290.
Our team confirmed several alterations in blood cellules, with the CSIC leader (MA Martín Requero); these alterations do not affect all NDD in the same way: they are clear in AD, moderate in PD, and absent in SLA
( Muñoz et al, 2008; Bartolomé et al, 2009; Esteras et al, 2013, 2015). With the Cajal Institute investigators
( Carmona et al, 2012 ) and with the CIBERNED team (E Carro) we detected biomarkers in AD ( Bermejo et al,
2010; Carro et al, 2017 ) and therapeutic possibilities with nanotechnology ( Spuch et al, 2010 ).
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stimulates cells to reproduce – impossible because neurons do not reproduce – the “two-hit theory”); or other theories such as that it is a mitochondrial disease or the physiopathogenetic hypothesis
154
. And as mentioned previously, some authors seriously suggest that it is exaggerated ageing.
And finally, as there are many curious people who read everything on the internet, it must be stated that there might be an infectious mechanism in the genesis of sAD
155
. It takes all sorts.
And so, an independent researcher has proposed an ingenious theory of AD that unifies nearly all of the hypotheses mentioned
156 .
154
The two-hit hypothesis for AD (Zhu et al, 2004, 2007; Herrup & Yang, 2007; Bonda et al, 2010, maintains that AD genesis
LVSUHYLRXVWRWKH$ ȕ RUWDXGHSRVLWLRQ$FFRUGLQJWRWKLVK\SRWKHVLVELRFKHPLFDODOWHUDWLRQV initiate mitotic changes (onset of neuronal division). However, this division in not possible in neurons and generates apoptosis (neuronal death) and other metabolic derangements that facilitate the deposition of badly
IROGHG SURWHLQV $ ȕ RU WDX ,Q WKH VDPH ZD\
Faa et al, 2014 , comment that multiple lesions (metabolic, infectious, inflammatory or toxic) during early brain development can produce a hit, imprinting or dysfunction that during brain development in childhood can be aggravated and appear during aging (in sAD and PD). There are many more AD hypotheses: synaptic alterations ( Terry et al, 1999 ; Cochran et al, 2014; mitochondrial alterations (Swerdlow et al, 2014; Boccardi et al, 2017), tauopathy ( Trojanowski, 2002 ) and many more
( Heininger, 2000 ; Nehls, 2016 ; see FN # 12). In the text of de la Torre, 2016 ; pp: 49-60, there is a nice review of the many AD hypotheses.
155
Fortunately, there are investigators able to search for every possibility. Itzhaki et al, 2016 , highlight the high frequency with which viruses or bacteria are found in the AD brain (necropsy). Could this finding be causal? The finding could be only the infectious adverse effect of AD brain fragility. However, the authors raise the possibility of treating people with AD with antiviral or antibacterial drugs. Recently, a book analyses this possibility, Miklossy, 2017 .
156
An independent German investigator ( Nehls, 2016 ) has released the unified hypothesis that includes the main putative RF related to AD and all the preventive measures…
79

To anybody unconnected to the therapy of Alzheimer’s disease (AD) it could seem that medical science and the pharmaceutical industry have not made enough efforts to investigate this subject. Nothing could be further from the truth. The number of drugs trialled in dementia and AD is very, very large (the treatment of AD has nearly 7,000 references on Medline , the database par excellence of biomedical citations) and there are numerous monographs
157
. It can be said that both the administrations that support research and the pharmaceutical industry have made an enormous investment of financial and scientific resources in order to achieve remedies for AD
158
. And not all of them have been failures. There have been some successes, as we shall see in this succinct review. But the fact is that a treatment has not been found, despite the economic and social benefits this would produce, not one that could cure, but rather one that would delay the appearance of AD by five years (its prevalence would decrease by half). There must be some reason for such difficulty... Readers who are not interested in the subject, which is biomedical, can skip the rest of the chapter, but they will miss some examples of scientific serendipity and surprising arguments, which could be of interest. This brief summary of medicinal therapy in AD only discusses the typical drugs of each therapeutic group and their physiopathological hypotheses on AD.
From the 19 th
century until the 1960s dementias, including AD, were conceived as diseases caused by inadequate cerebral blood flow. There are authors who still maintain this
159
. For this reason, therapies were developed to increase blood flow. The only treatment that was approved by the FDA was Hydergine
160
. This compound produced a slight improvement in the general alertness of the patient, in his mood, and a possible slight cognitive improvement, and if it did so, it was for a short time. It was tested on large samples of patients without finding important adverse side effects. Given its safety, the drug was used a lot as a therapy for senile dementia, including AD, until the arrival of calcium inhibitors and drugs that
157
In a review of main drugs (200) in AD trials 1984-2014, all had negative results, but four ( Schneider LS et al,
2014 ). Completed reviews of pharmacological treatment in AD: Anand et al, 2014 and Graham et al, 2017.
158
Cummings et al, 2014, 2016, comment that only in this century between 2002-2012, 413 trials in AD have been registered (124, Phase I – initial in volunteers –, 206 in Phase II (begin in patients), 83 in Phase III (in general, in patients and controls, phase previous to registration). Phase IV obtains safety data when the drug is in commercial use (78% of these drugs were promoted by pharmacological industry). The interested reader may visit the official USA database (www.clinicaltrials.gov). AD trials are an astronomical investment, not as high as in cancer, in spite of the social and economic cost of AD ( Wimo et al, 2014, 2017) and chap # 16 .
159
20
The vascular origin of senile dementias came from the 19th century and disappeared in the second half of the th
century. In the 90s, de la Torre, 1993 (and 2016) put this hypothesis on the causal table of AD again with some sophisticated data, and other authors refined the hypothesis (Zlokovic, 2011; Kalaria, 2009, 2012; Kelleher
& Soiza, 2013; see FN # 13 and 290. It is true that vascular brain dysfunction (clinical or subclinical) is an RF for sAD ( Snowdon, 1997, 2003; Hachinski, 2008; Morawe et al, 2012 ), but for many reasons it is unlikely that this could be its cause ( Bermejo-Pareja, 2018 ).
160
Hydergine, a co-dergocrine mesilate is a mixture of ergoloid mesilates, a derivate of ergotoxine. It was used from the 50s ( McDonald, 1979; Hollister & Yesavage, 1984; Markstein, 1989 ), first as cerebral vasodilators, and approved by the FDA (USA Food and Drug Administration) for treating some symptoms of elderly cognitive decline, and later for senile dementia. Hydergine has an almost complete absence of adverse effects, for that reason it was promoted in senile dementia over several decades. The first trial demonstrated that Hydergine was something better than placebo, but in the last meta-analysis (Olin et al, 2001) this finding was not clear.
Hydergine was not in trials for AD because the diagnostic consensus for AD diagnosis appeared in 1984
( McKhann et al 1984 ), and then, new drugs for AD were in trials: calcium antagonists and nootropics. For a review of these drugs read, Moos et al, 1988, with the name of cognition enhancers . AD drug treatment has produced an immense number of articles, and up-to-date reviews (e.g, Giacobini & Becker, 1997, Guiloff, 2001, and Candelise et al 2007 .
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enhanced the cholinergic neurotransmission of the brain ( figure 24 -19.1). These drugs that increase the cholinergic transmission of the brain are called anti-cholinesterases (ACI) because they inhibit the enzyme that catabolises (breaks down) acetylcholine, its neurotransmitter.
In the 80s it was already clear that the most common senile dementia was sporadic
Alzheimer’s (sAD). Various animal models showed improvement when they were treated with drugs that blocked the calcium receptors of cell membranes, which caused an increase in cerebral blood flow and neuronal neuroprotection. Nimodipine was the leader of this group of drugs, although due to its pharmacological constraints it was first used as a cerebral vasodilator; in fact, it is still used this way (vasospasm secondary to subarachnoid haemorrhage). It was also used for vascular dementia and strokes, because of its role as a neuroprotector in cerebrovascular lesions. As the data from animal models of ageing were brilliant, and as there were some encouraging trials in humans with dementia, it was used extensively in dementia and sAD. Nevertheless, the systematic reviews of its use for sAD have never shown clear efficacy. Also, many other medications, such as cognitive stimulants
(cerebral metabolic stimulants) were used in the 80s and 90s in dementia and AD
161
.
In these decades, the study of alterations of neurotransmitters , the substances that allow neurons to communicate with each other, was exhaustive in AD. From the 70s it was clear that in Parkinson’s disease there was a deficit of dopaminergic neurotransmission that was relieved by levodopa, so a neurotransmission deficit in AD was sought, that could be similarly improved with drugs. In 1974, some research suggested that there was a defect in cholinergic neurotransmission in AD and, finally, it was shown that neuronal depopulation occurred in the basal nucleus of Meynert
162
. This area is the source of cholinergic innervation of the cortex
( figure 24 -19.1). The hypothesis of cholinergic deficit as a causal factor in cognitive and memory disorder in AD received firm support. And this started a race to find drugs that could enhance this neurotransmission. In an intense competition, all the mechanisms of cholinergic stimulation were tried: from electrostimulation of the nucleus of Meynert to the administration of cholinergic drugs through injections straight to the brain (via the ventricular
CSF). The first to reach the finish line was tacrine (a medication of the family of ACI used in anaesthesia)
163
. It achieved this thanks to the studies of the doctor, WK Summers, who
161
The drugs that inhibited the calcium in the NS had several reviews ( Disterhoft et al, 1994 ), the main drug being nimodipine, used as a cerebral vasodilator (in CVD, Tomassoni et al, 2008 ). The finding that in mice nimodipine ameliorates several senile symptoms, promoted its use in human senile dementia ( Disterhoft et al,
1994 ). López-Arrieta & Birks, 2001, have reviewed this drug in dementia, mixed dementia and VaD and consider that it only produces significant effects in the short term. Recent data ( Nimmrich & Eckert, 2013 ; Peters et al, 2015) pointed out that cognitive enhancement drugs continued to be used in clinical practice. Schneider
LS, et al, 2014 , and Andrieu et al, 2015 reviews are good analyses of this field. Very recently, some nutraceutical foods (Souvenaid, Fortasyn Connect ) claim some AD symptom improvements, but global AD cognition is ameliorated ( Onakpoya & Heneghan, 2017; Soininen et al, 2017 ).
162
Drachman & Leavitt, suggested this in 1974. Later, British investigators confirmed this cholinergic deficit in
AD ( Davies & Maloney, 1976 ). Whitehouse et al, 1982, described the decrease of neurons in the basal Meynert nuclei that determine the cortical innervation. All this data supported the human cholinergic memory hypothesis
( Perry, 1988; Bartus et al, 1992 ).
163
Tacrine initiated ACI therapy. Summers et al, 1986, published an article with a trial with only 17 AD patients with nice results. This paper caused a scandal because it was the first publication of a new AD treatment, and the
FDA was severely critical of it (as was the Dean of Summer’s U). The drug was not approved ( Division of…,
1991 ). Subsequent trials were also negative, but a pharmaceutical company, Parke Davis (now disappeared), performed a very large and well-designed trial and obtained positive results and the FDA approved the drug
( Davis et al, 1992 ). More details of this fascinating story in: Olazarán & Bermejo, 1998 .
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published a pilot trial (funded by him) with only 17 patients and controls, in the prestigious medical journal The New England Journal of Medicine, concluding that the drug was effective in AD. The article was heavily criticised and caused a scandal. It led to an investigation by the powerful FDA and by the dean of the author’s university to see if there had been a scientific fraud... Such a fraud was not proved, although the trial was seen as flawed. Later, other authors carried out new clinical trials with tacrine, with a small number of patients; in these trials it was observed that the drug caused liver damage and they did not obtain clearly positive results. Then, a now defunct pharmaceutical company, Parke Davis, under the auspices of the FDA, managed to show its positive effects in this disease, in a trial that would lay the foundations for future clinical studies. The method used was a parallel group trial (AD patients are treated at the same time with the drug and a placebo in a system called double blind, as neither the patient nor the doctor know if they are taking the drug or the placebo); also, it used a very large number of patients in comparison with the previous trials. In this way, they managed to show the utility of the drug, which translated into a slight cognitive improvement. Although the improvement was limited, the trial marked an important milestone in a disease that had no proven therapy and raised the hopes of finding a pharmacological therapy for AD. Tacrine was approved in 1993. The success did not last long due to the difficulties in its use (hepatotoxicty). It was held back by other drugs that were approved at the end of that decade, starting with donepezil, which left other drugs of similar efficacy by the wayside, such as metrifonate (another ACI), which is toxic to the lungs. Thus, after great initial controversy over its efficacy, tacrine opened the way to the success of the cholinergic drugs (ACI), which restore the functioning of a cerebral cholinergic circuit, and which is used in the current day in AD. The aforementioned donepezil was followed by rivastigmine and later galantamine in the first years of the new millennium. No new AChEI drug has been approved since 2003. This group of drugs produces a modest cognitive improvement for a limited time: it is well demonstrated for six months, but does not usually persist for more than 1-3 years
164
, and it is symptomatic in nature in that they only have effect while they are being taken, like aspirin for a headache. They do not stop the progression of AD, although they very slightly improve the prognosis of its evolution.
Another drug that achieved success in therapeutic trials was memantine. It was approved in
2002 in Europe and 2003 in the US. It is a drug with a different action mechanism, which is only approved for moderate and severe AD
165
. Both the ACI and memantine produce symptomatic (while they are being taken) behavioural and cognitive improvement and the effect disappears when the drug is withdrawn.
164
After tacrine many ACI were trialled and at the end of the 90s and in the first years of the new millennium donepezil, rivastigmine and galantamine were approved. These ACI determine a significant improvement (10-
12%) in ADAS-cog (a cognitive test) in around half the AD patients ( Schneider LS et al, 2014 ), and some improvement in the IADL; its effects are statistically robust ( Birks, 2006 ), but clinically scarcely relevant and of short duration (6-18 months); donepezil has a positive study at three years ( Winblad et al, 2006 ). For some experts these medicines are not cost-effective ( Bond et al, 2012 ), although they have been approved by FDA and the European Medicines Agency 2008 .
165
Memantine has an interesting story: it is an antagonist of the NMDA receptors (neuronal stimulants) that was used for many years in Germany as a neuroprotector for several neurological interspecific ailments (dizziness and so on). A study demonstrated its utility in AD without a clear initial physiological explanation ( McShane et al, 2006). A case of scientific serendipity or pseudo-serendipity ( Roberts, 2010 ).
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The greatest amount of research, and also the most difficult and costly, into AD therapy has been the research into the development of medications that aim to modify the physiopathology of this disease, based on the amyloid cascade hypothesis, which is still dominant ( figure 25 -
,WPDLQWDLQVWKDWWKHGHSRVLWLRQRIWKHSRO\SHSWLGH$ ȕ LQVROXEOH in senile plaques (SP), located in the interstitial substance of the brain ( neuropile ), as well as
WKHIUDJPHQWVRI$ ȕ oligomers , soluble) or the grouping of these fragments ( protofibrils ), are
WR[LFIRUWKHEUDLQVSHFLILFDOO\WKH$ ȕ ROLJRPHUVZRXOGGLVUXSWW he neuronal synapses. These deposits would cause neurofibrillary degeneration (NFD) with the phosphorylation of tau (a protein that joins the skeleton of neurons or neurotubules ), and neuronal and synaptic loss.
Various groups of drugs have tried to eliminate the deposition of
$ ȕ DQGLWVROLJRPHUVIURP the brain. The aim is to improve or stop AD, by avoiding the amyloid cascade and thus
GHPHQWLD 7KH ILUVW WULDO DJDLQVW WKH GHSRVLWLRQ RI $ ȕ ZDV WKH IDPRXV LW UHFHLYHG D ORW RI publicity in the media) “Alzheimer’s vaccine”, which, as with all vaccines, was based on
LQWURGXFLQJ DQ DQWLJHQ RI $ ȕ WR WKH RUJDQLVP LQ RUGHU WR SURGXFH DQ DQWL
-
$ ȕ LPPXQH response that eliminates its deposition in the brain. The initial hopes turned to despair when the trial had to be suspended due to adverse side effects
166
.
Figure 24 (19.1).
Cholinergic brain neurotransmission
The transversal section of the brain shows the cholinergic innervation of the cerebral cortex which origin is the Meynert nuclei (subcortical). The functional restauration of this cholinergic circuit by
IAC drugs is the base of the therapeutic response of donepezil, rivastigmine and galantamine
The following drugs are genuinely biological marvels, almost from science fiction: humanised antibodies against
$ ȕ WKDW HOLPLQDWH WKH GHSRVLWLRQ RI WKLV VXEVWDQFH LQ WKH EUDLQ
166
The trial was suspended due to the adverse effects of the vaccination (immunological meningoencephalitis).
However, the necropsy demonstrated that in many anti-
$ ȕ vaccination treated patients, the
$ ȕ
deposition was eliminated, but in fact the patients died from the AD. There are reviews of passive and active immunotherapy
(drugs that eliminate
$ ȕ GHSRVLWV LQ WKH EUDLQ LQ
Wisniewski & Konietzko, 2008; Town, 2009 . Nevertheless, there are other therapeutic modifications to eliminate
$ ȕ GHSRVLWVLQWKHEUDLQDFWLQJRQWKHHQ]\PHVRI33$ metabolism ( Wolfe, 2008 and Anand et al, 2014 $' YDFFLQDWLRQ DJDLQVW $ ȕ GHSRVLWLRQ KDV KDG PDQ\ increasingly positive animal studies, but probably needs high amelioration to be used in humans ( Marciani,
2017 ). Currently, anti-tau vaccination is beginning ( Panza et al, 2016, 2017 ).
83

(bapineuzumab, solanezumab, gantenerumab and other similar drugs that impede this deposition). But despite the fact that these trials have been very careful and long (18 months), following the regulatory recommendations of the FDA and the EMEA, their results have not been positive, with possible exceptions in mild AD
167
.
This failure has generated not only a huge financial and scientific loss for the laboratories that promoted the trials, but also a heated theoretical debate. Two contradictory schools of thought have emerged: the authors who consider that the amyloid cascade hypothesis is not correct
WKH DFFXPXODWLRQ RI $ ȕ FRXOG EH QR PRUH WKDQ DQ HSLSKHQRPHQRQ DVVRFLDWHG ZLWK V$' which is gaining support faced with the failure of the trials, and those who maintain that the hypothesis is correct and that this would be demonstrated if a preclinical therapy against the
DFFXPXODWLRQRI$ ȕ FRXOGEHSHUIRUPHGDWOHDVWEHIRUHUHMHFWLQJWKHK\SRWKHVLVWKH\DUJXH we should try this test. That’s the way things are.
But it doesn’t stop there – there are many more physiopathological hypotheses on sAD: vascular, cellular oxidative stress, mitochondrial damage, tau toxicity, alterations of the cellular cycle of neurons, modifications of genetic RF (ApoE4), epigenetic, and others, whose analysis is beyond the scope of this monograph, and many of which have drugs in development
168
.
To finish up, we must highlight the fact that very powerful studies are still being performed with anti-
$ ȕ GUXJVRQSDWLHQWVDWWKHSUHFOLQLFDOVWDJHRI$'LHFRJQLWLYHO\QRUPDOEXWZKR exhibit biomarkers or RF of AD (ApoE4 positive, biomarkers in the CSF or in neuroimaging:
PET, MRI). The followers of the amyloid hypothesis and a large part of the pharmaceutical industry are still committed to the development of these drugs in cognitively normal people
(chapter 21). In four or five years, we will know who was right: the followers or detractors of this hypothesis. If this were a football match, they would be taking bets; the huge amount of
(senseless) advertising about betting on this sport is what leads us to think it reasonable to consider it... But it isn’t. In science, gambling does not usually give a clear and quick result, as in football matches.
167
These medicines (anti-
$ ȕ SRO\SHSWLGHV ZHUH UHFRPPHQGHG DIWHU WKH GHPRQVWUDWLRQ WKDW LWV WUHDWPHQWV L n transgenic mice decreased
$ ȕ GHSRVLWLRQ
( Schenk et al, 1999 ). Solanezumab has caused controversy. Its results in phase III were negative ( Doody et al, 2014 ) , but very mild improvements in AD patients were described in mild AD in a secondary analysis (Reardon, 2015). The polemic of this finding increased the previous controversy about the biological basis of this dru g (Becker et al, 2014). The controversy was ongoing ( Gandy &
Sano, 2015; Siemers et al, 2016), and in 2018 finished with the last negative trial ( Honig et al, 2018 ).
168
The dominant physiopathological AD hypothesis (which began with fAD) has been the “ amyloid cascade hypothesis” from Hardy et al, 1992, 2009, during the last 25 years ( Selkoe & Hardy, 2016 ). Today it has many critics for several reasons. First, the failure of anti-
$ ȕ GUXJVDQGVHFRQGEHFDXVHVHYHUDOELRORJLFDOGDWDQRW agree with it (e.g., Seabrok et al, 2007 ; Drachman, 2014; Whitehouse, 2014; Herrup, 2015 , De Strooper &
Karran , 2016 , Lista et al, 2016 , and Hunter & Brayne, 2018).
6HYHUDOLQYHVWLJDWRUVWKLQNWKDW$ ȕ LVDQHXURQDO by-product (neuronal metabolism residues) ( Drachman et al, 2014
RWKHUVFRPPHQWWKDW$ ȕ KDVQHXURSURWHFWLRQ functions ( Kumar et al, 2016 ). The existing data indicated a null causal hypothesis ( Lee et al, 2007 ), also there are many AD causal hypothesis (see FN # 154) . Nevertheless, the position that is mainly held is to trial against
$ ȕ GHSRVLWLRQLQSUHFOLQLFDO$'
(Dubois et al, 2007; Hardy, 2009, Sperling et al, 2011), although the preclinical sAD definition has been questioned ( Alexopoulos & Kurz, 2015 ). Amtul, 2016, comments that, nowadays, it is not clear which path to take. Many authors said that the amyloid cascade hypothesis persists because there in not another well accepted AD hypothesis .
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What has failed in the investigation of AD and its pharmacological therapy? The words of a director of the FDA resonate: “ It isn’t the methods, it is our ignorance ”
169
.
Figure 25 (19.2).
Cascade amyloid hypothesis
The amyloid precursor protein ( APP ), signal protein insert in the cellular membrane ( CM ) is catabolized (degraded) for enzymes ( scissor
2QHFDWDEROLVPIUDJPHQWLV ȕ $DQGLWVROLJRPHUV$Q
LQFUHDVHRI$33I$''RZQV\QGURPHRUWKH ȕ $RU ȕ $ROLJRPHUVZRXOGSURGXFHWKH ȕ $GHSRVLWLRQ in form of SP with the later appearance of NFD , neuronal and synaptic dysfunction, and neuronal death
169
See the criticisms of D’Alton & George, 2011 , Herrup, 2015, De Strooper & Karran , 2016 , about the biological reductionism of the amyloid cascade hypothesis, and also from the supporters of systems biology
( Wood et al, 2015 ; Lista et al, 2016). Finally, read the title of the text of Leber, 2002 .
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Yes, there’s no doubt that memory stimulation exercises do some good. But let’s take it one step at a time. The question that specialists hear every day is whether these memory maintenance exercises, which in Spain are promoted by councils, communities, and care homes and day centres for the elderly, can delay the appearance of dementia or Alzheimer’s
(AD) in cognitively normal elderly people. And the second common question is whether they can prevent its progression in people with memory impairment without dementia. And a third issue: when a person has dementia, do memory exercises and cognitive stimulation do any good?
170
Let’s start with the last question, as this has been studied the most.
Non-pharmacological therapies (NPT) encompass a miscellany of procedures (from cognitive stimulation to aromatherapy , table 8 (20.1) proposed for the treatment of patients with dementia and AD, which have been studied with varying rigour. These therapies are common in day centres as well as care homes for the elderly, and patients with sAD. Day centres are the ideal place for studying the efficacy of these memory stimulation activities, cognitive training and functional training (exercises in activities of daily living), both individually and in groups; also for various cognitive rehabilitation techniques. As there are so many studies, it is better to summarise them using the systematic reviews (see glossary). “And what do these systematic review studies say?” In brief, stimulation with different exercises or with various cognitive techniques is beneficial for the emotional stability of the patient and of the family.
The positive effect is found both in techniques such as reminiscence of the patient’s past and in cognitive stimulation based on computer tasks; also in simple techniques (reality orientation, which aims to help the patient orient himself in place and time) and in more complex techniques such as multi-component intervention. These therapies show benefits in the patient’s behaviour, stabilising him cognitively and functionally for some time. It can be said that NPT are beneficial, in general, not only for the patient, but also for his family, among other reasons, because it gives them a break from continuous care
170
.
170
The first question asks if the memory exercises and other techniques (NPT) could delay an illness, in this case dementia, (primary prevention). The second question is if a patient that has the beginning of an illness (memory disorder, MCI), whether the NPT exercises prevent the full appearance of the dementia illness (secondary prevention). The third question is if the patient with the established (dementia or AD) illness could be ameliorated by NPT, that is to say tertiary prevention, or in simple words, therapy, to impede dementia progression. In the next chapter, FN # 178 gives more explanations about the concepts of prevention in
Medicine.
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Table 6 (20.1). Non-pharmacological therapies (NPT) in dementia/Alzheimer &
Mainly cognitive
Cognitive training *
Cognitive stimulation *
Cognitive rehabilitation *
Reality orientation
Reminiscence therapy
Validation therapy
Recreational activities
Psychotherapy and Support therapy
Memory training
Behavioural interventions
ADL training
Physical exercise
Use of music
Luminotherapy
Miscellaneous
Aromatherapy
Transcutaneous electrical stimulation (TCES)
Massage and touches
Muscle relaxation
Multisensory stimulation
Acupuncture
Transcranial magnetic stimulation
Domestic animal stimulation
Multicomponent stimulation (several associated therapies)
& Modified from Buchert et al, 2010 and Olazarán et al, 2012.
*Mild differences according to Buchert et al, 2010
“Beneficial... OK... but how beneficial?” Well, the problem of quantification is difficult in a progressive disease like sAD and, above all, with such diverse techniques that are studied in such different ways. In summary it can be said that the benefit achieved cannot be generalised across the whole spectrum of therapies, because if it were possible, the authors of systematic reviews would be in agreement, and they are not. In medicine, when authors do not agree, it means the issue is not clear. In this case, neither the scope of the benefit of certain therapies nor which of all the NPT is most useful is clear. It seems that cognitive stimulation exercises, in a broad sense, are beneficial, but have a minimal impact on maintaining cognitive performance. Also, it has been shown that if NPT are carried out in patients that are being treated with acetylcholinesterase inhibitors (ACI) or memantine, the effects of the drugs and the NPT are additive. NPT are especially useful for patients who suffer from psychiatric, emotional and behavioural disorders. In addition, NPT seem to be more positive in rehabilitation conditions, i.e. if they are performed so that a patient adapts to a specific place,
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such as his own home, and if the rehabilitation is carried out by expert therapists, preferably with the collaboration of relatives. When they are simply performed in an abstract or theoretical scenario, for example when the aim is to recognise and recall words from a list, the generalisation of the effect to other contexts or simply to daily life and their effects on the recovery or maintenance of memory are minimal, if they exist at all. We can say that it can be more useful to encourage the maintenance of functional capacity in a stable environment than to perform purely cognitive tasks (attention, memory, reasoning) in order to increase or maintain mental performance (memories, intellect). Nevertheless, the three latest reviews on the subject do not agree
171
. The most optimistic review was carried out in 2010 by a German team; it concludes that these therapies are positive, above all on healthy elderly people, and they have biological repercussions in the brain. Another systematic review presents more moderate results. It was led by a Spaniard (J Olazarán) with an international team in 2010; to summarise, it considers that NPT is clearly proven and is highly recommended for carers of patients with dementia (grade A conclusion – high evidence – which means that the proof given is very solid); for the patient, some NPT are recommendable but with less evidence
(grade B), specifically cognitive stimulation and training, and multi-component therapies (i.e. diverse types of cognitive therapies and functional components). There is either no evidence, or it is very limited, for other therapies (acupuncture, transcutaneous electrical nerve stimulation – TENS – aromatherapy, music therapy, recreation therapy, support psychotherapy, etc.). The review recommends group sessions due to their practicality and low cost. Lastly, the most recent review of these therapies is the one performed by the authors of the Cochrane collaboration (2013), which only deems functional rehabilitation reliably proven; as for cognitive stimulation exercises, it recommends more studies in order to scientifically substantiate their benefits
172
.
Another factor in favour of NPT in groups of patients is the improved relationship between cost and efficacy in comparison with pharmacological therapies, and they are supported by the British NICE in their clinical practice guidelines and by the Spanish Ministry for Health
173
.
171
It is clear that the treatment of a dementia patient also has an effect on the family and more so with the types of therapy in which the family participation is more complex than administering a medicine. In reality, many dementia patients visit day centres or live in nursing homes. Both locations are ideal places to perform NPT because in both there is a gathering of many elderly people. In addition, in both places it is possible to carry out studies on people affected by MCI, dementia or AD, even on cognitively normal subjects. However, NPT trials are not easy to carry out for many reasons. The efficacy of NPT has generated many systematic reviews without unanimous agreement. Lautenschlager et al, 2014, published a panoramic study of this field.
172
The studies mentioned are Buschert et al, 2010 (German) ; Olazarán et al, 2012 (international, whose leader was a Spaniard); and, Woods B et al, 2012 and Bahar-Fuchs, et al, 2013 (Cochrane reviews). The German study was a review of NPT in healthy elderly people and at the same time discussed NPT studies in MCI, AD and recommends longer trial duration (18-24 months) to obtain better conclusions on its utility. The Olazarán et al,
2010 , study analysed 26 AD NPT, and after that, the authors recommended, according to the Oxford Centre for
Evidence-Based Medicine, which NPT is best for each patient type . Its conclusion is that NPT are cost-effective in AD. Example recommendation: cognitive training is better (B-grade recommendation, – evidence moderate) than cognitive stimulation, a different conclusion from Bahar-Fuchs, et al, 2013; nevertheless, the Cochrane authors accept cognitive rehabilitation with moderate evidence.
173
The reputed British NICE, an institution that supervises the quality of medical assistance, has given several dementia recommendations. The 2017 booklet is difficult to summarise, but briefly, is mildly favourable to NPT in dementia and AD; mainly for cognitive and behavioural symptoms, but it demands more trials. The last update of the USA ARHQ ( Kane et al, 2017 ) maintains that there is moderate-strength evidence that cognitive training improved performance, but only in the trained cognitive domains. Many specific reviews annotate aspects of
88

In summary, it can be said that NPT are useful in the general therapy of AD and the dementias, although not all are equally useful. Intervention strategies focused on rehabilitation and daily living activities have shown their efficacy in clinical trials more clearly than those just based on cognitive training. Sadly, barring exceptions, the efficacy of NPT on dementias only persists while the therapy is taking place. On the positive side: the low cost in relation to efficacy when performed in groups and, in general, they improve the quality of life of patients and carers. Despite all this, they do not impede the progress of sAD
174
.
In pre-dementia (MCI), NPT have also been used, and although there have been studies with hopeful results, such as those focused on the cognitive training of memory, behaviour and emotions, the systematic reviews have not been positive on subjects with MCI (they could delay the functional decline of these patients, but not the cognitive decline).
The data are of interest, without doubt, but not very comforting. But, in favour of these NPT, it must be emphasised that many emotional and personal nuances are almost impossible to measure, and also that they contribute to increasing the interaction between the patient with dementia (or MCI) and his family (or carer). Both feel comforted and have a better quality of life – difficult qualities to capture with biomedical evaluation
175
.
It is clear from studies with healthy elderly subjects that training, cognitive stimulation and physical exercise are more beneficial than for those with MCI or dementia. Several studies
(SIMA and ACTIVE among others)
176
have shown improvements in cognitive domains
(memory, reasoning, speed of mental processing) after long periods of treatment; some of these improvements persist for more than five years. These results are important to support the view of cognitive and functional therapies as primary prevention in sAD. Moreover, they support the statement in the first paragraph that “Yes, there’s no doubt that memory stimulation exercises [and NPT] do some good”. But, it’s a “yes” with many caveats.
NPT: reality orientation ( Spector et al, 2000); cognitive rehabilitation (Clare & Woods, 2004); validation therapy (www.vfvalidation.org), neuropsychiatric therapy ( Ayalon et al, 2006); association of NPT and drugs
(Requena et al, 2006); cost-effectiveness (Knapp et al, 2006) and ACI medicines-NPT (Bond et al, 2012 ) and others. The improvement of patient dignity with certain NPT (validation therapy) is a very well described in
Whitehouse & George, 2008; pp:102; and website: www.vfvalidacion.org.
The Spanish Ministry of Health ( Ministerio de Sanidad…, 2011 ), developed CPG on dementia (assessed by many collaborators, the author of this monograph included). These CPG recommended following the Cochrane collaboration NPT in dementia and AD.
174
Some studies demonstrated that the improvement could persist for one year ( Willis et al, 2006). Physical exercise as a NPT in dementia and AD has reviews ( Farina et al, 2014; Kane et al, 2017; Leshner et al 2017), also about individual or in-group psychotherapy (Cheston & Ivanecka, 2017 ).
175
Several NPT have produced positive results, some cognitive or emotional, in predementia ( Belleville, 2008;
Troyer et al, 2008; Kinsella et al, 2009 ), but the systematic reviews are sceptical ( Williams et al, 2010; Cooper et al, 2013; Kane et al, 2017 ). The functional evolution in MCI patients is favourable in the systematic review of
McLaren et al, 2013 . More studies of long duration are needed.
176
The SIMA study ( Oswald et al, 1996 ) and Willis et al, 2006 have shown the clear efficacy of cognitive training in normal subjects. More recent studies ( Barnes et al, 2013; Lee KS, et al 2014; ACTIVE study
( A dvanced C ognitive T raining for I ndependent and v ital E lderly ), Rebok et al, 2014, confirm the previous data and raise the possibility of preventive trials in AD ( Solomon et al, 2015 ). The AHRQ review ( Kane et al, 2017 ) and other wide systematic reviews ( Blazer et al, 2015, Lechner et al, 2017 ) consider cognitive training a promising activity in the dementia prevention field. The Buschert et al, 2010 review gives biological plausibility to these procedures.
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Yes and no. The fact that currently there do not appear to be any curative drugs, or at least, drugs that detain the evolution of Alzheimer’s disease (AD) does not mean that they could not exist in the future
177
. But, in the meantime, prevention of AD is a modest but safe value, and we must commit to it. A bird in the hand...
“But weren’t there a lot of medications to prevent AD being studied?” Before delving into this subject, it is worth defining what prevention is. It is obvious that prevention is the therapeutic strategy with which to seek to impede the appearance of a disease, in this case dementia or
AD. And, if its appearance has to be impeded, the disease is not present. Do you remember the figure about the evolution of sAD ( figure 3 -5.1)? Right, then, depending on the moment when the preventive strategy is applied, it is categorised as: primary, in the case of AD, when there are no symptoms (normal memory and cognition); secondary – it is performed when the memory loss or cognitive decline have already started (pre-dementia, MCI, or other definitions); and tertiary when the patient has the disease, but the aim is for it not to progress, for it to be slowed down or to be cured. In MCI and dementia pharmacological and nonpharmacological therapies (NPT) have been established (see previous chapters), although when the dementia is obvious, we do not usually talk about tertiary prevention, but rather treatment of the disease
178
. We have already seen the trajectory of this tertiary prevention
(chapters 19 and 20) so we shall examine the primary (no symptoms) and secondary (with pre-dementia) preventive strategies performed with drugs.
A recent review
179
analysed 47 completed prevention trials and 74 that were in progress. In both the completed trials and those underway, many preventive strategies have been tried: drugs, nutritional products, foodstuffs, control of cardiovascular risk factors (CVRF), and
NPT (chapter 20): physical exercise, cognitive stimulation, among many others. Also, many combined or “multi-domain” therapies have been tried, i.e. the combination of two or more preventive strategies. (Summarised in table 9 -21.1). Don’t be alarmed, we are only going to discuss a summary of the most significant actions and their foundations.
“And what do these clinical trials tell us?”
Many drugs for the prevention of the development of dementia in prodromal AD (MCI or predementia) have been trialled. A systematic review , which divides up the pharmacological and
NPT interventions, makes it clear that within the pharmacological therapies, high quality studies have been carried out with ACI (donepezil, rivastigmine and galantamine), all without success (including another with memantine associated with an ACI and with piribedil (despite the results with animal models) and various medications: anti-inflammatories (NSAID);
177
The possibility of obtaining new medicines with the capacity to delay AD, prior to 2025, is minimal according to the experts, especially for disease-modifying therapies ( Cummings et al, 2016, 2018 ).
178
Fletcher et al, 1988, de Irala-Estévez et al, 2004 , analysed these concepts (see FN # 170). The comments given in this FN were from the clinical perspective; from a biological approach it is necessary to bear in mind that primary prevention must be performed in people without any clinical or biological deficits (biomarkers or neuroimaging). Another type of prevention is primordial prevention that refers to society (e.g., to ban guns prevent murders; pollution elimination to prevent bronchitis). The preclinical AD definition has not yet reached consensus ( Khachaturian et al, 2016 ).
179
See the review of Schneider LS, 2014 ; the exhaustive review of Andrieu et al, 2015 and the most recent review of Graham et al, 2017 .
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fluoxetine; medicinal herbs (ginseng in several preparations, another Chinese herb, Dan Shen
Yin, and gingko biloba); vitamins B and E; omega-3 fatty acids; grape juice; and green tea, to mention the most significant. No drug, medicinal compound or foodstuff has achieved its goal of delaying the appearance of AD in comparison with a placebo. Nevertheless, some of these pharmacological strategies are associated with small cognitive improvements
180
. In addition, numerous NPT have been used: cognitive stimulation with various methods (including with a computer), psychological stimulation with memory training (with calendars and photos) cognitive and behavioural NPT (reminiscence therapy, psycho-motor and recreational activities, among others), as well as psychological intervention in groups and in the family, and physical exercise. All the results obtained with these methods have been negative or inconsistent (chapter 20), although it is true that many of these studies had neither the duration nor the number of patients necessary to produce clear results
181
. This negative assessment of the pre-dementia (MCI) studies has encouraged trials aimed at preclinical or pre-symptomatic sAD (no cognitive impairment, but with positive biomarkers in the CSF or in neuroimaging), with the theoretical basis that if there is no therapeutic response when dementia is established or in pre-dementia (the long trajectory of AD is known, figure 3 -5.1), there might be a response when sAD is incubating. As there are no sure biomarkers in sAD, this is a highly difficult task.
“So what to do?” One proposal is to study populations which in medical jargon are called selected or enriched, i.e. with clear risk factors (genetic or CVRF) and investigate whether the therapeutic strategies impede the appearance of sAD in comparison with controls from these populations who are not treated. The problem with these clinical trials of primary prevention is that their design, choice of strategies, and selection of participants are complex. They must be designed carefully, include a large number of participants (several thousand), have a long follow-up period (5-10 years) and choose drugs that do not have adverse side effects (it is unethical to include healthy subjects, even though they have RF of sAD, if the chosen therapy carries some health risk)
182
.
In general, it can be said that there are two main kinds of preventive trials: those that are going to try to eliminate
WKHGHSRVLWLRQRI$ ȕ RUWDXXVLQJGUXJVRQFOLQLFDOO\DV\PSWRPDWLF subjects; and those that have the ultimate aim of reducing the incidence of dementia and AD
180
In the previous Chap there is a comment on MCI therapy to prevent dementia/sAD. Minimal cognitive improvement with several drugs (e.g. nicotine patch in non-smokers improves attention, Newhouse et al, 2012 ); with some nutraceuticals, Rondanelli et al 2012; Chiu et al, 2008, and Sinn et al, 2012 described memory and emotional states getting better with several oils that could be confirmed with new studies. The NSAIDS trials
( ADAPT Research Group, 2007 ) were negative; ginkgo biloba raises hopes because it did not have adverse effects, but several studies ( DeKosky et al, 2008; Vellas et al, 2012), and one systematic review , Charemboon &
Jaisin, 2015 , did not show action to prevent MCI or dementia. Other reviews on this subject: Andrieu et al, 2015, and Rafii &Aisen, 2015. In conclusion, dementia and AD are not prevented with MCI therapy (Kane et al, 2017).
181
Launer, 2005, 2015 comments on the theoretical and practical difficulty of preventive trials in AD.
Furthermore, in one recent systematic review, Canevelli et al, 2017, pointed out that SES is not evaluated in the great majority of the AD RCT performed.
182
Meanwhile, Hauber et al, 2008 performed a survey: many Americans are ready to accept risks in AD preventive trials only if the suffer early AD manifestations. Nevertheless, from an ethical point of view, a healthy person could be trailed with drugs whose efficacy is being studied. Carrillo & Vellas, 2013, have revised the requirements for participants in AD preventive trials with drugs and NPT. In addition, an international agreement about the requirements for these trials for patients and drugs ( Molinuevo et al, 2016 ) has recently been released.
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with multi-dimensional methods (NPT, reduction of CVRF, with or without drugs, and with the modification of lifestyle: physical exercise and diet).
6HYHUDOWULDOVZLWKGUXJVWKDWDLPWRHOLPLQDWHWKHGHSRVLWLRQRI$ ȕ RUWDXDUHEHLQJSUHSDUHG and some are already in phase 3, the phase that tests the efficacy of a medication. In general, they are sophisticated trials, on populations with clinical peculiarities. One, called “A4”, is studying solanezumab on subjects with a heavy load of amyloid in the brain. Three other trials are focused on people who carry the genetic alterations of fAD and who are at risk of developing a clinical picture of dementia from fAD in 5-15 or more years. And there is another trial on sAD with homozygous carriers of ApoE4 (with two “4” alleles, one from the mother, the other from the father), whose genetic risk of suffering from sAD in the future increases. In both cases, various anti-
$ ȕ GUXJVDUHEHLQJXVHGLQFOXGLQJQHZPROHFXOHVVXFK as crenezumab, solanezumab and gantenerumab, and new vaccines which are, in theory, free from adverse side effects)
183
. Also, several multi-dimensional clinical trials are being carried out, in general using NPT strategies. The trials that stand out among these are the European trials being carried out under the auspices of the EDPI (www.edpi.org), which are an international collaboration (between three countries) that includes three large populationbased cohorts. These cohorts are divided into treatment and control groups and the aim is to prevent MCI, dementia or sAD. The Finnish study, FINGER, uses multi-dimensional actions
(nutritional, control of CVRF and others); it is a randomised study on 1,200 participants who will be followed for seven years. The preDIVA study, promoted by the University of
Amsterdam, will follow a cohort of 3,534 people for six years; two types of therapy will be trialled: in the control group, the normal treatment will be administered, and in the other, a specific therapy will be used (nurses who monitor pharmacological therapy, lifestyle and
CVRF). Finally, the MAPT study is being carried out in France, with intervention over a period of three years and a follow-up of five years, on a cohort of 1,600 elderly people (70 and over); mainly, they are given advice on nutrition and physical activity
184
. There is also a project underway (HATICE) based on (randomised) therapeutic advice in the three participating countries (Finland, The Netherlands and France), which is performed on the
Internet. In the FINGER trial there are already some encouraging data: the group of treated
183
Preclinical trials are reviewed by, Rafii & Aisen, 2015, and Andrieu et al, 2015, and recently by Graham et al,
2017 and Lane et al, 2018 ) . Summarising the main trials: a) A4 ( Anti-Amyloid in Asymptomatic Alzheimer’s , in phase III) compares solanezumab versus placebo in 1,000 participants. b) DIAN-TU ( Inherited Alzheimer’s
Network-Therapy Unit ) trials several anti-
$ ȕ
drugs in 160 fAD genetic positives ( Bateman et al, 2016 ). c) API-
ADAD, PS1 gene asymptomatic carriers in Colombia with ages (30, 40 and 50 years with possibilities of fAD development would be treated with crenezumab ( see Lock, 2013; pp: 142-43; for a clear trial description and interesting comments). d) API ApoE4 in 1,600 participants, homozygotes of ApoE4, that will be treated with active immunotherapy and anti-
$ ȕ
drugs. These trials included many participants and will be of long duration.
Anti-tau therapies are being developed - these therapies are more difficult because NFD are mainly in the neuronal soma ( Sigurdsson, 2009; Folch et al, 2016 ), but could be necessary ( Iqbal et al, 2014, 2016 ).
184
Trial references (see table 9 ). FINGER ( Finnish Geriatric Intervention Study to Prevent Cognitive
Impairment and Disability , Ngandu et al, 2015).
PreDIVA ( Prevention of Dementia by Intensive Vascular Care ) whose results with 3 years of follow-up have been negative (van Charante et al, 2016).
MAPT ( Multidomain
Alzheimer Prevention Trial , Carrie et al, 2012, and Vellas et al, 2014) ; HATICE (Healthy Aging Through
Internet Counselling in the Elderly ) program to obtain the participation of 4,600 elderly to prevent CVD and dementia in a randomised trial performed online (HATICE, www.hatice.eu). More information in: Imtiaz et al,
2014 ; Solomon et al, 2015, Bermejo-Pareja et al, 2016 b, and Graham et al, 2017.
All these trials are multicentre, with random selection (MAPT is the exception), different design, and multicomponent (CVRF control, diet, exercise and others) therapy. Some of then finished in 2015, and in 1-3 years the results are expected (FINGER has published alluring preliminary results, Ngandu et al, 2015 ). There are registries to plan new prevention trials ( Johnson et al, 2018; Vermunt et al, 2018 )
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participants performed better in cognitive tests than the control group. Table 10 (21.2) shows a brief summary of these trials. Performing these trials involves making a great effort, scientifically, financially, and in terms of international co-operation, which aims to qualify and quantify the importance of prevention of dementia and sAD.
Table 7 (21.1). Clinical trials for sAD prevention
&
Pharmacological
ACI and memantine drugs
-Donepezil, rivastigmine, galantamine and galantamine + memantine
Anti-hypertensive
-Several combinations
Nutraceutical
-Vitamin B complex and folic acid**
-Vitamin E and flavonoids
-Omega-3 and other fish grease acids
-Diets
NSAIDS
-Indomethacin, naproxen, celecoxib, rofecoxib, triflusal and others
Hormones substitution*
-oestrogens and progesterone
Miscellaneous
-Ginkgo biloba
-Glycaemic control ***
Non-pharmacological therapy (NPT)
Cognitive stimulation or cognitive training
-Several methods
Specific cognitive training
-Memory and/or other specific cognitive domains
Physical exercise
-General and specific (aerobic, walking, by-cycling, yoga and others)
-Combination of multiple types of physical exercises
Non-pharmacological multicomponent
-Cognitive training and aerobic exercise
-Multicomponent life style modification (Physical exercise, cognitive, diet and other), supervised by experts
-CVRF control, Physical activity and others****
& When the patient suffer cognitive decline, MCI, predementia
*In women; **that decrease homocystinemia; ***in diabetics **** included drugs
NSAIDS: Non-steroidal anti-inflammatory drugs
Modified from Andrieu et al, 2015
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Table 8 (21.2). European trials of primary prevention of dementia and AD*
FINGER Finland
Preventive measures Years (age)
Multicomponent 1,200
PA, Di, CVRF*, CT 60-77
Primary Objective
5
Dementia incidence preDIVA Holland Multicomponent 3,533 6
PA, Di, CVRF* 60-78 Dementia incidence
1.680 5
Multidomain & omega-3 >70 Cog performance
Abbreviations: PA: physical activity. Di: diet; CVRF: Cardiovascular risk factors; CT: cognitive training; Cog: cognitive
*Summarized; Trial references in FN # 184
The practical conclusion: the prevention of sAD must be implemented – it is recommended by more and more authors
185
, and one author sums it up with this simple verdict: “If the drugs fail, let’s look toward prevention”
186
.
185
Opinion leaders such as: Khachaturian et al, 2009, 2011; Carrillo & Vellas , 2013 and experts: Barnes &
Yaffe 2007; Imtiaz et al, 2014; Norton et al, 2014; Sindi et al, 2015.
186
Rice, 2014, summarises his thinking with a radical phrase .
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This chapter is long and important, so it has been divided into six sections to make it clearer.
The aim is that it can be read by any reader, which limits the biomedical information but makes it more accessible. Also, the content of the chapter is less well-known than other aspects of sporadic Alzheimer’s (sAD), is more general than neurological, and includes social issues
187
; ageing and dementia are social issues not only because of their consequences, but also because they represent agents of risk of both. The disease cannot be reduced to biological aspects; as we shall see, psychological, familial, social and even cultural connotations are involved in the disease. If this chapter is read with care, it will be easier to understand why prevention of sAD must be started at a very early age.
22A. Does the family of the future child have anything to do with Alzheimer’s?
The title may seem provocative or pretentious and that’s why it has been framed as timid question. Many will think that it is because of the genes that the family contribute to the newborn child. They’re on the wrong track. Genes are important in sAD as in all diseases, but we’re not going down that route. This chapter talks about familial context and its importance in the genesis of diseases. Yes – something purely familial and social, not genetic. Medicine has paid more attention to biological aspects of disease than to social aspects (the former have been the basis of its quantitative scientific progress), but when one part of the set of causes of disease is put in the spotlight, the other parts – the social and psychological aspects – get left in the shade. It’s time to shine a light on them: we humans are hugely social primates – hence our progress.
The family has been an important nucleus for social life and caring for offspring since time immemorial. De facto, many human biological aspects originate from family organisation.
Thus, it should not be surprising that looking after offspring in the family environment has an influence on the appearance of certain illnesses, and even the length of life. For the doubters, here’s a surprising story about primates. The marmoset, a likeable primate, has a peculiar family organisation. It’s the male that looks after and takes charge of the infants and the female deals with other tasks; well, the life expectancy is higher in the males than the females.
Let’s take some other species of primate. In several types of gorilla, the care for and feeding of the baby gorillas is a task shared equally between male and female, and the life expectancy is similar for both sexes. In humans (and chimpanzees and other small monkeys), it is the woman who looks after the children and life expectancy is higher in women, in practically every culture in the world. How can we explain this biological difference generated by the social sharing out of tasks in the raising of offspring? Well, it’s easy: over thousands and thousands of years, genetic selection has favoured the survival of women because they have been more necessary for the species
188
. And from birth, females have lower mortality than
187
Social conditioning and socioeconomic disparities (in nutrition, education, environmental problems such as pollution, toxicity or social hostility) could be causal agents of illnesses in human groups ( Brunner et al, 1999;
Marmot et al, 2012 ). Mainly, when these problems are persistent. Neurological disorders and AD must be included among the consequence of these causal agents ( Moceri et al, 2001; Karp et al, 2004; Wilson et al,
2005; Hackman et al, 2010 ; and Raizada & Kishiyama, 2010 ).
188
Social conditioning and socioeconomic disparities (in nutrition, education, environmental problems such as pollution, toxicity or social hostility) could be causal agents of illnesses in human groups ( Brunner et al, 1999;
Marmot et al, 2012 ). Mainly, when these problems are persistent. Neurological disorders and AD must be
95

males (although more males are born than females, after a few years of life there are more girls than boys, and it stays like that… until widowhood; in Spain survival of women was about seven years greater than that of men until very recently).
This generic introduction makes it easier to understand how the familial and social context can modify human biological aspects and also to understand the development of the brain.
Studies in animals and humans have shown how the familial and social environment can significantly influence the development of the brain and this is a subject of prime importance in the neurosciences.
Let’s start with the studies in experimental animals: baby rats that are given care and attention by their mothers exhibit larger dendritic trees in the neurons that control cognitive aspects
(hippocampus and frontal lobe) and greater brain development that translates mainly to better learning and memory. In various rodents and non-human primates, artificially invoked stress
(reduction in the access to food and other methods) to females during pregnancy leads to reduced care and attention to the baby after birth and less suckling and stroking of their offspring. This lack of attention produces changes in their young – in the neural systems and in the hypothalamic-pituitary-adrenal axis, which regulates the stress response, which can persist throughout life and can even be transmitted to future generations by epigenetic mechanisms. More examples of this can be found in various diseases and in cognitive and emotional development
189
.
These examples show that the title of this section is faint-hearted and also restricts the origin of many illnesses to the family when often it depends on society, populations and nutritional history: many diseases go beyond the limits of the family. And for the ever present and sizeable group of disbelievers – it’s good to be sceptical in scientific matters – let’s continue with more examples. One example comes from the book “What makes us human?”
190
. The author describes how it can be explained that a country like Finland, which in the last 3-4 decades has taken a lot of care to control cardio-vascular risk factors and which currently boasts good socioeconomic development, has a mortality rate from myocardial infarction four times greater than that of France. The explanation given is not familial, nor even does it hold the Mediterranean diet or delicate French cuisine responsible. It is the nutritional history of both populations over many decades. Childhood malnutrition produces a child who biologically has a thrifty phenotype
191
and, logically, the vast majority of that population suffers from poor nutrition. Chapter 1 described how this (biologically) childhood phenotype increases, in adulthood, the likelihood of diabetes, vascular and neurodegenerative (NDD) diseases like sAD and ageing. So what are the nutritional histories of Finland and France?
Well, they’re very different. It must be remembered that the Finns lived in poverty until 50-60 years ago. And, poverty leads to childhood malnutrition (and the thrifty phenotype of the foetus). This phenotype would take 2-3 generations to turn into the developed or opulent phenotype. In France, this was not the case; in fact, after the Franco-Prussian War of 1870, included among the consequence of these causal agents ( Moceri et al, 2001; Karp et al, 2004; Wilson et al,
2005; Hackman et al, 2010 ; and Raizada & Kishiyama, 2010 ).
189
Consult the reviews of Hackman et al, 2010 in animals and humans, the article of Liston & Gan, 2011 , about stress in animals and the interesting review of Hanson & Gluckman, 2014 .
190
191
Ridley, 2004, in his informative text, documented this fact very well.
See Hales & Barker, 2001 and their explanation of the thrifty phenotype (FN # 98).
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the diet of pregnant women was supplemented by order of the French government. The
French generations of the last century did not suffer childhood malnutrition (as a generalised phenomenon) and this difference can explain the differing mortality from cardiac diseases until the Finnish generations habituate biologically (plausibly, this could take several generations) – the mysteries of the mechanisms of intergenerational transmission ( soft heredity ) and epigenetic-environmental interaction.
Some could think that the example given is an isolated case, but nothing could be further from the truth. There are many similar examples, some of which will be described later. These anecdotes are useful to make clear the importance of the social environment in the development of complex diseases , including sAD.
Shall we start with the family? With the education in the family environment? Or with its wealth/poverty, or socioeconomic status (SES)? Let’s look at the closest thing: the parents and the general family environment.
Could anyone think that the weight of the mother has an influence on the weight of her recently born baby? And that of its grandmother? Perhaps the majority of readers would say no. And they would be wrong: yes, they have an influence. If you went up to someone in the street and asked them if they thought the educational level of their mother could be in any way related to there chances of developing dementia in old age, no doubt they would think you were mad, and they would almost certainly be annoyed (it’s not a good idea to mention someone’s mother or her education). And they would be wrong too about whether the education of the mother or father has more influence on the future cognitive performance of the child. I think most would say that of the father or of the family unit. Let’s give some answers. The weight of the mother (and possibly that of the grandmother) influence the weight of the child that is going to be born (in normal conditions, obviously). This is what has been called intergenerational transmission (which is not genetic, but rather epigenetic and perhaps has some cultural component)
192 and which depends on the environment (foetal malnutrition of the grandmother can be transmitted over several generations, as with the
Finnish population’s malnutrition). Well, yes, maternal education has been related with the chances of dementia in several studies, such as the ADAMS study
193
. Also, the education of the family unit has more influence on the future cognitive performance of the child than the affection of its parents, but the latter (and a good family atmosphere) have more effect on emotional and behavioural development than the educational level of the family. The answers to questions about the mother’s lifestyle and the future health of the child are affirmative: her behaviour and lifestyle before, during and after pregnancy, in the following months, are greatly important to the development of the brain of the child. And these factors depend on her educational level according to the aforementioned study and, perhaps more importantly, well-educated mothers will look after their children better and will have daughters who know
192
For non-believers it is worth reading the works of Brook et al, 1999; Kaati et al, 2002 and Brown JM, 2016 .
All of these showed that the maternal line transmits some metabolic traits intergenerationally; paternal line transmission is very infrequent ( Pembrey et al, 2014).
193
The Aging, Demographics, and Memory Study (ADAMS) carried out an investigation of 857 elderly people, by American and British authors ( Rogers et al, 2009 ). This survey analyzed a selected sample of retirees, aged
70 and above, with a cognitive evaluation and ascertaining their socio-familial background. Its conclusions are: the offspring of mothers with fewer than 8 years of education have more risk of future MCI or dementia; and the attributable risk in these groups of mothers with a low level of education is as high as 18%.
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better how to protect their children starting from pregnancy and will reduce their future risk of dementia and sAD. For the fathers who feel disappointed by these findings, I can offer them another case-control study that shows that fathers who have capacities higher than an unskilled manual labourer give their children a lower risk of dementia in the future
194
.
The family SES is also important. Social inequality also generates inequality in general health, with higher mortality in the most underprivileged classes
195
. There are numerous studies that reveal that the health and cerebral and cognitive development of the child depend to no small extent on the SES in which the child finds himself. This brain development is influenced by the prenatal environment, and obviously by pregnancy, and later by parental relations and the cognitive stimulation that this environment creates. As has been described, the studies in animals have shown that if recently born baby rats are raised in a cage, they develop much worse than those brought up in a standard environment, who in turn develop worse than those who grow up in an enriched environment (changing toys, complex mazes, basically Disneyland for the little creatures, in a nice community), who develop their cognitive capacities better. The data on humans indicate that being born into a family of low
SES brings with it, largely, an environment with worse health, often with more stress in the family members, and cognitive and emotional difficulties which frequently persist throughout life, or remain hidden and develop several decades later
196
.
To sum up, the family, its SES, the health of its members, the education of the parents, above all the mother, and its emotional environment all have a bearing on the future development of the child, on his health and specifically on his cognitive development, his cognitive reserve and in future decades they have an impact on the appearance of dementia and sAD.
194
The case-control study of Moceri et al 2001 , reconstructs the familial and childhood story of 926 sAD cases in Seattle, USA, and finds the following RF of dementia: father being an unskilled manual worker, large family
(seven or more members) or to be a carrier of APOE4. Another two surveys ( Everson-Rose et al, 2003 and
Wilson et al, 2005) obtained a relationship between the proband family SES and their cognitive performance in old age, but not with cognitive decline (dementia was not evaluated).
195
Examples in UK, Marmot et al, 1991; in Spain, Regidor et al, 1994 ; in Europe, Marmot et al, 2012; and in
USA, Adler & Rehkopf, 2008 .
196
Hackman et al, 2010 , showed the consequences of low SES in humans. These consequences are well described in the book of a neurologist and neuroscientist, the son of a gynecologist, Swaab, 2014 . Raizada &
Kishiyama, 2010, analyzed the difficulties of brain development in people with low SES, and their psychological problems, Bradley & Corwyn, 2002 . A detailed Finnish study confirms the importance of SES in cognitive development throughout life ( Kaplan et al, 2001 ). With respect to sAD (even the aforementioned Moceri et al,
2001 and ADAMS), Shonkoff et al, 2009 show how when health disorders appear, they should be taken back decades before, because their root is, frequently, low family SES and chronic personal stress.
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Table 9 (22a.1). Risk and preventive factors for sAD in the family &
Familial Risk factors
Father and mother (mainly) education (RF less than 8 years of education)
Deficient mother health (nutrition and life style)
Father work: manual worker
Familial socioeconomic status (SES)
-low SES is associated with:
---Hyponutrition risk, and alcohol, tobacco, pollution (air and others) exposure
---Parental style with minor cognitive (language) offspring stimulation
---Higher vital stress, higher alostatic family and offspring burden
---Worse general health of the family
---Possible brain development of infant (with several-associated RF)
RF: Risk factor; Preventive factor inverse to RF
& Elaborated with data of several authors, see text
22B.The prenatal period – be careful during pregnancy
The importance of the foetal period in metabolic and brain development has been demonstrated little by little over the last three decades by continual studies and observations.
The scene for the new vision for chronic and complex diseases was set with the discoveries of
Barker and his team (chapter 1). They gave rise to his hypothesis about foetal programming of the development of various non-communicable diseases (NCD) and complex diseases in adults: myocardial infarction and cardiovascular diseases (CVD), obesity, high blood pressure
(HBP), diabetes (DM2), and cancer among others. The hypothesis points out how the environment of the baby (the womb) and not just heredity and adult lifestyle was fundamental to its development. The roots of the baby’s development lie in the prenatal environment
197
.
Perhaps this is the moment to give a new more novelistic example than the methodical investigations of Barker, which is, nonetheless, no less scientific and very interesting. In 1944 the Dutch resistance to the invasion of the German army brought about a rail workers’ strike whose aim was to prevent German reinforcements from arriving in the city of Arnhem (of great strategic value due to its bridge over the Rhine) but the Nazi commanders reacted by putting an embargo on all the private vehicles in the country, which led to a food shortage in a large part of The Netherlands and a famine that caused 10,000 deaths, and which was called the “Winter Famine” (1944-45). There were about 40,000 pregnancies in this period and many of them resulted in death of the baby or foetal malformations and many babies were born underweight. This fact created a tremendous “natural experiment” because it was a famine limited to a short period of time (around six months) in a population without chronic
197
David Barker was a pioneering clinical doctor and epidemiologist. He demonstrated with great tenacity over three decades that foetal hyponutrition (environment of poverty) have several manifestations in the baby (low length, weight, and cranial circumference) that in the future could be associated with higher CVD mortality and greater NCD incidence (HBP, DM2, osteoporosis and others). He collaborated with Australian and American experts to study several foetal aspects in NCD and underlines that these types of investigations must be prioritized over genetic research. Taking care during gestation and infancy would be a necessary social investment, and he demonstrated it, designing studies about this in the Third World. The environment (maternal womb) could initiate the risk of several diseases (NCD) that were attributed to genetic or to unknown factors
( Fall & Osmond, 2013 ). An exemplary scientific trajectory.
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hunger (neither before nor after – an event that has not happened in current or past famines in
Asia or Africa). It is not surprising that numerous researchers have studied (and continue to study) the cohort of 2,414 live births from this period ( Dutch Winter Famine Birth Cohort -
DWFBC ) that had medical records of the state of nutrition at birth. The (very full) examination of the evolution of this cohort has produced valuable information, in general in agreement with Barker’s hypothesis. In the DWFBC cohort, in those born with signs of malnutrition, there has been an increase in mortality from CVD, cancer and breast cancer
(only in the girls), and also, an increase in obesity and diabetes has been observed (above all if certain genetic features were associated), along with an increased frequency of HBP and hypertensive response to stress. The underweight children had a smaller brain (which shows that foetal malnutrition affects the development of the brain) and lower cognitive performance
( attention and executive tests ) when they reached the age of 56-59 (the age of the participants when they were examined), a greater incidence of schizophrenia and major depression
(diseases originating in the brain) and greater inactivity in old age (only in men), which suggests accelerated ageing in malnourished children. Actually, the findings are more complex than this summary (there are variations according to sex and the period of pregnancy in which starvation was experienced, with the third trimester being the most critical). Also, intergenerational transmission of metabolopathies has been detected (the risk has reached the second generation), meaning that the daughters of women who were starved during the first six months of pregnancy, even though they had a birth weight within the normal range, gave birth to unusually small children. The risk of sAD has not yet been studied
198
.
The Spanish population starved, above all in the cities, during the Civil War and post-war period, even more in the years 1937, 1940, 1943 and 1945 (the year of starvation). A group of researchers has shown that those born in these years have an increased mortality from ischemic heart disease in comparison with those born in nearby years. So the Spanish study supports Barker’s hypothesis about foetal programming of CVD
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Let’s move on to some more examples. Is there anyone who believes that if the mother smokes during pregnancy, her child has more chance of being fat? Or if the mother has a diet high in fish (free, of course, from the mercury that large fish have), then the child will have better cognitive performance? Surprising as it may seem, the two situations come from scientific studies and are true. The consequences of smoking during pregnancy, above all if the mother smokes more than 20 cigarettes a day or before the 15 th
week of pregnancy, are multiple (10% prematurity, greater risk of foetal death, worse brain development); the beneficial results of eating fish (it contains polyunsaturated fats which are not synthesised by
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These findings are delightfully narrated in the books of Ridley, 2003 , and Swaab, 2014 . The birth cohort of
Holland famine period ( Dutch Winter Famine Birth Cohor t - DWFBC) has the characteristics of a natural experiment. Many investigators studied this cohort confirming in some way Baker’s findings and sustaining the
DOHaD postulates (FN # 2). In addition, it has generated about 60 Medline articles with, to our minds, the most important being Roseboom et al, 2006 , health data; van Abeelen et al, 2012 , survival and mortality; de Rooij et al, 2010, 2016, about cerebral size and cognitive performance; and Bleker et al, 2016, about ageing.
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González Zapata et al, 2006, analyzed the famine in the Spanish Civil War, and its associated subsequent increase of CVD mortality.
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the body) are just as clear – it is associated with lower prematurity and other positive effects
200
.
Perhaps the moment has arrive to leave the examples behind and describe well-proven hypotheses that maintain that it is not only our lives that start in the womb, but also health, the risk of suffering from certain non-communicable diseases (NCD) and complex diseases , such as heart disease, obesity, and DM2 among others. The study that Barker and his team began in the 80s, which demonstrated that signs of foetal malnutrition (low weight, size and cranial circumference) are associated with various NCD in middle age, generated the foetal origin of adult diseases (FAOD ) hypothesis. This hypothesis later became the developmental origins of health and disease hypothesis (DOHaD) after finding that not only was the foetal period the start of risk but also that development during infancy (in some cases up to adolescence) was a critical period for the development of this risk, which was a new observation on the causality of these diseases
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. The proof for the importance of the DOHaD in the genesis of NCD has much more support than the examples described (coming from various cohorts such as the large Helsinki cohort (HBCS), the famine study (1959-61) in China and others in Europe,
Africa and Asia (see footnote)
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. Also, DOHaD has scientific support from animal research: in rodents, in the yellow-skinned agouti variety of rat, which is very sensitive to diet and in other breeds; in several medium-sized mammals – goats whose pregnancy is similar to human pregnancy; and in non-human primates, which have confirmed the importance of mal/hypernutrition during pregnancy and childhood and the risk of appearance of complex metabolic disorders (diabetes and obesity). Just one succinct example to express the complexity of
DOHaD: if a female baby rat is injected with a male hormone (testosterone) five days after birth, its development will be normal but when it reaches puberty, it will not ovulate; but if it
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Capra et al, 2013, described the illnesses and maternal lifestyle that could affect the foetus. Eliminating toxic habits (tobacco, alcohol), and doing physical exercise and having a healthy diet are important points for foetal development; they concluded that anomalous events, such as hyponutrition during pregnancy can produce epigenetic modifications that influence the vital development of the new being. Scarce nutrition could determine the thrifty fetal syndrome , which in the adult period, if abundant nutrition existed, could increase the likelihood of obesity and DM2 ( Hales & Barker, 2001). In addition, foetal hypernutrition could increase the likelihood of obesity and DM2 in the future ( Vickers, 2014 ). Hyponutrition is a severe problem in the Third World due to its importance in brain development and because it is an RF for NCD ( UNICEF, 2011 ; de Onís, 2015; GBD 2016
Risk Factors Collaborators , 2017 ). In addition, alcohol ( Chokroborty-Hoque et al, 2014; Ilomaki, 2015 ) and tobacco exposure ( Banderali et al, 2015) could be deleterious. Many FR exposures (metabolic, infectious, toxic) by epigenetic or cerebral mechanisms could facilitate the beginning of NDD and sAD ( Faa et al, 2014 ). It has been described that fish intake during pregnancy is associated with less risk of prematurity and low weight of the new being ( Jedrychowski et al, 2010). Small fish and shellfish: prawns, sardines, anchovies, salmon, etc, are rich in omega-3 and have no mercury; but large fish such as tuna and swordfish have high mercury content, which is unimportant for adults but possibly harmful for the fetus and must be eliminated from the pregnant mother’s diet
( Bambrick & Kjellström, 2004).
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The DOHaD (Developmental Origins of Health and Disease) hypothesis (www.dohadsoc.org) has adequate scientific support in animals and humans with physiological and epidemiological data ( Gluckman et al, 2006,
2008 ; Wadhwa et al, 2009 , Hanson et al, 2011, Hanson & Gluckman, 2014; Heindel et al, 2015 (FN #, 2 and
198).
Several cohorts, the previously mentioned Hertfordshire, UK and DWFBC, and, in addition the Helsinki
Birth Cohort Study (HBCS) support its postulates. HBCS is formed of more than 20,000 children born between
1924-44, who had biomedical birth data and long follow-up to old age. HBCS has generated about 200 Medline publications. As examples: Kajantie et al, 2005, that analyses HBCS mortality data ; Eriksson, 2016, summarising the main findings. There are others investigations in this field. The Chinese great famine of 1959-
61 ( Kim et al 2017 ), and others ( Wadhwa et al, 2009; Fall & Osmond, 2013; Hanson & Gluckman, 2014;
Sparre-Sørensen et al, 2015 ).
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Bateson, 2001, analyses the famine consequences of the siege of Leningrad, 1941-44, (now, Saint Petersburg again). The main consequences affected starved pregnant mothers and infants in analogous ways, both having subsequent risk of NCD.
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is injected on the 20 th
day of life, this will not happen. This example shows the importance for health that environmental forces have and the delicate relationship between the action and the moment of development that the action (hormonal in this case) occurs
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.
“What about the relationships between foetal malnutrition and the brain?” Well, there are data on animals. When experimental rats are malnourished, their offspring can be born with disruption to the cerebral cortex and other parts of the CNS and also a reduction in the number of neurons has been observed. “And are there any data on humans?” Yes, there are many studies that relate prenatal conditions with cognitive performance in children and adults, but few in the elderly. There is a British study, which shows how those affected by malnutrition at birth have lower performance in cognitive tests in old age. Also, there are data from the aforementioned Dutch DWFBC and the Finnish HBCS – the latter reports greater cognitive deterioration in old age for malnourished children. The data on their association with dementia and sAD are still scarce
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Let’s pick up the thread of the importance of the first years in the risk of NCD again.
Malnutrition is very important in the first two years of life as if this occurs (which is common in the Third World), it can increase the future risk of these diseases. Also, the first two years of life are greatly important for brain development. In these years, connections are established that are very important in their relation with environmental stimuli, as we shall see in the following section (23C). Furthermore, in the first 5-6 years, the brain reaches more than 90% of its final size. These facts have given rise to investigations that relate brain size, intelligence and risk of AD, which would indicate that brain size is a predictive factor of future cognitive performance (brain reserve), whose importance would increase if the individual had other associated RF: genetic (ApoE4), low level of education and physical inactivity. And it is in this period that the brain is shaped, with myriad neuronal connections being established, and the cerebral cortex being structured according to contact with the environment (section 23D).
In this context it can be understood that the development of the brain in the first years is as important as foetal brain development or even more so
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Let’s go back to the beginning: the mother. Research on the start of infant risk in complex diseases has shown the importance of the nutritional state of the mother prior to pregnancy
(including abdominal fat), of her diet during pregnancy, and how these factors affect the composition of the body of the baby. According to the nutritional conditions, the foetus
“programs” its future metabolic adaptation, helped by the genetic information in its DNA and the epigenetic information transmitted by its parents (mainly the mother) about their own environmental (nutritional) metabolic experience. This allows the foetus to establish the physiology of its immediate metabolic future. In this programmed physiology that the foetus establishes, other maternal environmental factors are greatly important: her diseases, the size of the placenta, maternal stress that could generate endocrinal responses that lead to resistance to insulin (DM2), obesity, and other factors. It is worth remembering that there is a long list of illnesses that the mother could suffer from: physical (asthma, DM2, infections), psychological
203
Hanson & Gluckman, 2014, Eriksson, 2016.
204
See Gale et al, 2003 (British study) and Raikkonen et al, 2013 (HBCS). To review the first moments of life
(intrauterine and postnatal) and their relationship with sAD and dementia, read Borenstein et al 2006 , and Seifan et al, 2015.
205
See Gale et al, 2003.
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(stress, depression) drug treatments (thalidomide is a paradigmatic but extreme example), addictions (tobacco, alcohol, marihuana, drugs), exposure to environmental toxins (lead, air pollution, mercury), and her lifestyle (physical exercise, diet – mal/hyper-nutrition). All of these are part of the foetal environment and contribute to its metabolic programming
(unconscious, of course)
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.
How would this foetal programming be produced? Well, it would depend on the environmental context – in an adverse context (poor nutrition) the foetus would favour the development of certain indispensable organs (the brain is protected, due to the principle of economy) at the expense of others (e.g. muscle, lungs, kidneys, liver), which could cause subclinical disruption to the foetal organs that would manifest themselves later
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But in
Western societies, maternal hyperalimentation is common (10-20% of pregnant women are obese or suffer from DM2), which increases the future risk of the baby suffering from these disorders, and even their transmission to the next generation (epigenetic)
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It must be stressed that the foetal brain is extremely sensitive to neurotoxins (the placenta is a very labile barrier, which allows small molecules to pass: carbon monoxide; or those soluble in fat: alcohol). Many toxins, which are not harmful to the mother, can disrupt the formation and migration of neurons in the delicate foetal brain. For example, the mercury contained in large fish such as tuna or swordfish, or the toxins (pesticides) that accumulate in the fatty tissue of the mother, when released into the blood, can be passed to the foetus. The very low weight of the foetal brain and its structural “tenderness” mean that the potency of these toxins is 100 times greater than in the mother
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The pen can be cruel and this cruelty has prevented mentioning other important aspects of pregnancy and foetal life, but I can’t resist mentioning one. We have already seen that the foetus develops a biological memory, but does the little foetal brain have a cognitive memory? This is open to debate. Dalí said he remembered everything that happened in the womb, but apart from the lysergic mind of this brilliant and extravagant painter, is there any truth in foetal memory? Well, yes, the foetus stores memories of sounds (the mother’s voice), vibrations, smells and tastes in the uterus, which remain with it after birth. Years later, these memories will be wiped, as with the memories of the first years of life: childhood amnesia
(nobody remembers what happened up to the age of 3-4, exceptionally 2). And as this is the case, Dick Swaab says ironically: the foetus must not be exposed to dissonant sounds of arguments or bad TV programmes… It is undeniable that the lifestyle of the mother (activity, diet, leisure, musical taste) has repercussions in the foetal brain
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. This is why it is crucial for the mother to be careful during pregnancy. The dangers for the foetus are manifold and the
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FN # 200 discussed the importance of maternal diseases; the role of the placenta is discussed by Hanson &
Gluckman, 20014 ; and an exhaustive analysis of the harmful role neurotoxins to the foetus is given by
Grandjean et al, 2006 , 2007, which brings to mind the Paracelsus quote: “poison is a question of doses”. For the tender brain in development, a minimal dose of a toxin could be a poison in the present or the future. There are data on animals and humans on this subject ( Wu et al, 2008; Dobbs, 2009; Faa et al, 2014 ).
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208
Recent review of the physiological changes: Hanson & Gluckman, 2014 .
Hajj et al, 2014, studied the effects of maternal hypernutrition in animals (mice) and non-human primates
( Vickers, 2014; Hanson & Gluckman, 2014 ).
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210
See the excellent review of Faa et al, 2014 .
Read Swaab, 2014 and Chap # 23 c. It is not clear that the intrauterine first year’s memories are completely wiped from the brain, perhaps some of them could persist unconsciously ( Li et al, 2014 ).
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mother must control them; the family and society have to contribute to making all pregnancies
“happy pregnancies”. The child’s brain will thank them for it for the rest of its life.
22C. Childhood and youth: we have to get the sapling to grow straight
The development of the foetal brain is very important, as serious lesions are difficult to repair, but brain development in infancy is even more important, both quantitatively (the weight of the foetal brain is 300-350g and the adult brain weighs 1250-1500g, and in the first 5-6 years more than 90% of this weight is reached) and qualitatively, since during the period of infancyyouth the “connection” between brain and environment will be established – an interaction that, as we shall see, also has very important critical periods for its proper development
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In chapter 1 it was stated that computers and brains work in very different ways. And this is true. In order to explain how the human brain is integrated with the environment we can use a simile (only a simile) with digital culture (in whose revolution we are immersed). Let’s consider the brain of the child who is born as if it were a computer with all the necessary applications pre-loaded: packages for writing, making slides, calculations, going online, sending emails, and even joining social networks or watching YouTube . But in order for this computer (prepared with its programs – like the human brain with its genetic information) to work, various actions are required: decompressing applications, loading them into memory, and performing various manoeuvres to set them going, connecting to the web, and even restarting the computer. If we don’t do all of this, the applications won’t work. In the same way, the child’s brain is born with genetic potentialities to suckle at the breast or bottle, to see, to speak, or to attune to the family emotionally. However, the truth is that from the moment of birth, the child has to start learning about its feeding by suckling at his mother’s breast or the bottle and begin to recognise the taste of food, the faces of family members and their emotional connotations, which reflect their emotional states… He will learn little by little, first by non-verbal interaction with family members, which will give rise to his joy, smiles and tears. This learning is slow and has hits and misses (The computer simile is not complete – the computer can be set up in an hour while the “switching on” of a baby takes years). And soon he will start to learn an important code: language. In order for all the cognitive capacities that he will be learning to work, the baby’s brain needs to interact with the environment (familial, social and biological) and develop
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. Some behaviourists posited that the infant brain was like a blank slate on which the environment could write its codes and mould the brain
213
. But it’s not like that: the infant brain is born with many genetically
211
The paradigmatic example of learned behaviour is the new born duck that follows the first figure it sees when it open his eyes, in general the mother duck, but exceptionally a man (Conrad, a famous behaviorist). Apart from this anecdote, the hypothesis of the brain as a tabula rasa (blank slate) , on which is possible to write the new being’s behaviour is false. The Steven Pinker, 2011 monograph rejects this hypothesis with arguments that convince the reader.
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Several monographs in Neuroscience (e.g., Purves et al, 2011 ) discussed the subject: in addition, reviews
( Blows, 1999 , in only three pages) and Johnson MH, 2001 defined the field and it is very interesting to read.
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The gap between brain development and the hippocampus growing in the first years of life determines the phenomenon called infantile amnesia: missing episodic memories of the first 2-4 years, apparent in children from 6-7 years of age, which persists in adults and throughout life. J osselyn & Frankland, 2012 described the neurobiological basis of this phenomenon; in brief, the human hippocampus has a very slow development, its neurogenesis is slower but more persistent that the rest of the NS; this slowing alters the initial neural memory network. Bauer & Larkina, 2014 explained the clinical characteristics of this process. Nevertheless, several refined studies in animals and humans demonstrated that these memories are not missing from the brain, even though they are not conscientious remembered ( Li et al, 2014; Travaglia et al, 2016). Several interest related
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predisposed possibilities to be developed, but it needs contact with the environment in order for the pre-established circuits to work (the simile is just a simile). The infant brain can’t have something for which it is not prepared stored on it, only what can be stored, and this must happen at the exact time (critical periods) that the machinery of the neural connections requires. For the child to be able to see and understand what he sees, he must have visual contact with reality: light, the faces of his mother and family, which he learns to recognise
(and this must be at the right time – there are examples of children born with congenital cataracts (blind) who did not have them removed at the right time, but rather at the age of 10-
12, who began to see once they were removed but could not interpret what they saw – they were functionally blind). If children are not spoken to, they do not start to speak (it’s as simple as that, as we shall see later) and the same is true of the rest of the senses. Sensory contact is necessary for the brain to attune to the environment and this contact is multidimensional – the child sees and plays with a toy and these sensations are incorporated into the cerebral cortex, which is as yet little structured. It is not possible in this monograph to describe the marvellous deployment of neurons which occurs in the first years of brain development (neuronal and glial). The neurons are born and arrange themselves radially in the cerebral cortex like the soldiers in a little army, each of which knowing where he has to go (in this case guided by the glial cells). And, the neurons’ multiple synaptic connections are established ( dendrites like the branches of a tree; axons like the trunks) with existing neurons or with others that are being born. Those that fail to make connections and are not integrated into the neuronal circuits die ( apoptosis ). Contact with the environment: light, touch, language and other sensory and emotional stimuli enhances and reinforces these neural circuits, and gradually more localised cerebral areas form where diverse cognitive capacities are integrated
(initially they are diffusely arranged in the cortex). Later, the myelinisation of the axons occurs, which gives the wiring of the brain much faster connections
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. One clinical consequence of these evolving changes during the restructuring of the brain in the first years is what is known as childhood amnesia : the curious disruption of memory which means that the first infant memories are wiped as the child’s brain grows (and new synaptic connections are formed in it until the age of about 6-7). This forgetting continues into adulthood (we do not remember anything before the age of 2-4). This is an undesired consequence of the great brain development of the first 5-7 years of life and of the slow development of our hippocampus – the structure where memories are “woven”.
We have mentioned that for the infant brain to develop its cognitive capacities properly, there is a critical period, after which it is not possible to incorporate the environmental information received, although the formation of the brain is not completed until one’s 30s (with the myelinisation of the prefrontal areas – figures 7 (6.4) and 8 (6.5). These critical periods also exist for the metabolic maturation of the child. Let’s see some examples. In order not to suffer the undesirable consequences of infant malnutrition (obesity, diabetes, HBP) the window is works: Akers et al, 2015, Spalding et al, 2013 and Bergmann et al, 2015 , these near to science fiction; and the latest review of Anacker & Hen, 2017 (See chap # 6, and FN # 58).
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de Onís, 2015, analyzed Third World infant hyponutrition and explained the necessity of its eradication to prevent NCD, mainly, infant obesity, which obviously needs adequate diet and physical exercise (5-17 years), and also avoiding the abuse of sugar-laden drinks. UNICEF, 2011, showed that pregnancy and the first two years of life are the most critical 1,000 days of life . During these days, the basic development of the infant occurs.
Any care deficit (nutrition, emotional or others) will affect health and cognition throughout life . WHO, 2013, ratified this statement and there are several accessible articles: Pem, 2015 .
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the first two years. Proper cognitive development also requires normal attention to be paid
(cognitive stimulation) in the first 2-3 years. Another example: if children born from normal pregnancies and births do not receive the usual care and attention in the first two years after birth (as has happened in cases of children left in orphanages), these children do not learn to speak properly and suffer from mental retardation. In addition to this, if children abandoned by their parents are put up for adoption in the first two years of life and thus receive normal attention from a family, they develop well cognitively. But if they are adopted after the age of two, even though the adoptive family treats them with love and gives them the normal cognitive stimulation, they do not (statistically) achieve normal cognitive development. Let’s extend the examples to some extreme cases. Cases have been described (not many, but they have been well studied, above all in the 18 th
century) of children who have lived without normal human contact during long periods of their childhood. If this period exceeded 10-12 years, they would never manage to speak properly, nor would they develop normal intellectual capacities. (Some horrifying examples are described in the footnotes)
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.
To sum up, during the first years, connections are formed in the human brain, which are necessary for brain functioning in relation with the environment. In these connections, the brain incorporates its cognitive capacities and crucially, language, one of the important human achievements that is going to be developed soon. In the uterus the child already begins to recognise his mother’s voice and during the first months the child starts to understand basic aspects of his mother’s language. In this first year he starts to say the odd word, which will become two or more towards the age of two, and he will be able to make short sentences by the age of three (there is quite a lot of variability within the normal range). The period of basic learning of language finishes around the age of 12. If the child has not received adequate verbal stimuli (the case of the “wild children” mentioned) he can no longer learn to speak, nor can he learn a foreign language without an accent. Needless to say, an environment rich in verbal stimuli and intellectual attention are of great value in the first years for the learning of language and cognitive strengthening
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. It is also worth pointing out that we must not
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There are several examples from antiquity of children deprived of human contact (language and emotional).
The first is attributed to an ancient Egyptian King (Psamtik I) who put two newborn infants in the care of shepherds with the instructions that they should not be taught to speak. More cruel and extensive experiments are attributed to James IV of Scotland and mainly to Frederik II of Prussia. This king (18th century) wanted to determine what kind language newborn infants deprived of human contact would speak. No child spoke, all of them died or were grossly retarded (https://en.wikipedia.org/wiki/Language_deprivation_experimentss). In modern times, there are very few confirmed examples of “feral” or “wolf” children reared without human contact (no cases were clearly proven). The best study is a French child, Victor of Aveyron, who appear in the forest of Languedoc (1797) probably aged ten. He was studied by a doctor, JM Gaspard Itard, who tried to educate him, but was only able to say “ lait ” (milk in French) and never had normal cognitive capacity. More recently, the famous and terrible story of 13-year-old Genie (mother blind, paranoid father, and permanently chained to a bed) who was found in California in the 70s. When she was discovered, the father committed suicide. The teenager was raised with psychologist attention was never able to speak, although she acquired some intellectual qualities ( Cutiss, 1977 ). These dramatic stories are described brilliantly in the books of ( Ridley,
2004; Swaab, 2014 ), and specifically in Leary, 1984 and LaPointe, 2004. In addition, there are interesting studies in non-human primates ( Capitanio & Mason, 2000 ).
The long impressive text of Bowlby & WHO, 1952 , showing the critical nature of social contact in the first years of life, now has the experimental confirmation in the Bucharest study ( Nelson et al, 2011 ; Fox et al, 2017 ).
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Many studies describe the influence of the environment on the child’s cognitive development (Swaab, 2014).
Exposure to the mother’s and family’s language and emotional stimuli are very important, mainly in the 6-10 months after birth (the baby only recognizes and learns the phonemes in a social context). If the instructor is a
TV or a radio, the baby will not learn ( Kuhl, 2010, 2015 ). The baby begins to recognize the mother’s language from the third trimester in the womb ( Friedland, 2011 ); Krueger & Garvan, 2014 discussed this subject very precisely.
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exaggerate in the baby’s learning (reading him many stories that he does not understand); children develop properly in a normal environment. “Verbal hyper-care” – daily readings to the baby in order for him to learn to speak – does not enhance his intellectual and language development, but rather can impede it due to stimulation overload; it is not recommendable
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.
It must be stressed in this description of cognitive and cerebral formation that, in this infant period, not only is the brain formed, but also physiological and metabolic frameworks are established in the whole body, and this will be relevant to future health and illness (the biological capital of general health is established in infancy)
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Are there risk factors (RF) and protection factors (PF) for the appearance of dementia and sAD in this period of infancy-youth? Well, there are studies (not too many) and some important reviews about the relationship between this period of life and the appearance of dementia and sAD that show that adversity of any kind during early brain development
(dyslexia or language difficulties, an environment scarce in food or educationally, and in brief, a poor socioeconomic status – SES) are associated with more incidences of dementia and sAD in old age
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.
The importance of SES in many investigations
220
is striking, above all in the mechanisms with which it influences the course of life, above all with a very low SES, i.e. poverty
221
.
Possibly this result is due to an adverse social trajectory throughout life, but the issue is debatable and some authors explain it with biological mechanisms associated with low infant
SES. What is true is that poverty affects the child in various ways (education, infections, environmental stress, psychological trauma, friends, school, neighbourhood, family health and other constraints) and it is difficult to separate these components. In fact, animal studies on the consequences of “ cognitive enrichment ” (various games and mazes for the baby rats) or environmental deprivation (isolation in a cage) are fairly easy to perform, in contrast with human studies. And, of course, there are biomedical data on the subject. Perhaps the most
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Bruer, 1998, described this subject clearly for the general population.
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WHO, 2013, considers the infancy period to be basic to future health (FN # 216), stating that health is established in the first years of life by multiple mechanisms, biological, social environmental and epigenetic. In this period breastfeeding is very important ( Anderson JW et al, 1999; Angelsen et al, 2001 ), as well as general nutrition, education, environmental aspects and others ( Rice & Barone, 2000 , review this subject in animals and humans) and Faa et al, 2014 the mechanisms that could initiate NDD.
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To understand the risk factors for dementia and sAD in this period the studies of Borestein et al, 2006, Seifan et al, 2015 and Whalley, 2015 (excellent monograph) are relevant. Two expert epidemiologists in dementia
( Breteler, 2001, and Launer, 2005) have underlined the importance of infant development and the necessity for more studies in this field.
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S ocioeconomic status (SES) is a battlefield in neurobiological research on the brain and the genesis of elderly memory decline ( Marder, 2017 ), NCD and NDD ( Hackman et al, 2010; Hanson & Gluckman, 2014; Johnson
SB et al, 2016; Farah, 2017). The innovative study of Noble et al, 2015 , from California, analyzed the relationship between familial income and the dimensions (logarithmic) of the cortical area. In deprived infants, small modifications of the family income have repercussions in the dimensions of the global cortical areas and in the specific cortical zones related to language, reading, and executive and spatial functions. See Moceri et al,
2001, and FN # 184 and 197, in which the relationship between SES and sAD is discussed .
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Poverty is a pervasive condition all over the world, including developed countries (in Spain around 22,2% of children suffer from poverty and 7,4% are extremely poor) according to FOESSA, 2014 . Worse still, the Spanish data demonstrated that poverty is transmitted over generations, perhaps only 20% of people born poor manage to escape from this situation ( Bedoya, 2016, FOESSA & CARITAS, 2013, 2014) . More alarming are the USA data: around 40% of the children could be considered poor or near poor and one in five are truly poor ( Johnson SB et al, 2016 ).
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developed of these, due to the duration, come from a Scottish study: the Aberdeen cohort.
Those born in 1921 and 1931 were evaluated cognitively when they were 11 years old for an educational study of Scottish schoolchildren. The survivors who gave their permission were examined again in 1998 (with psychometric tests and complex neuroimaging examinations: fMRI and brain necropsy). It is not possible to describe all the findings, but we can conclude with three aspects of this investigation: a) the association of a smaller hippocampus (its role in memory is known) with a lower SES; b) cognitive performance (intelligence) in childhood correlated with later adult performance; c) using complex calculations on the fMRI scans, the authors maintain that cognitive reserve (measured by the childhood cognitive tests ) protects against vascular and AD-type lesions in old age. Examination of the synapses of normal subjects (with the brains obtained) in this cohort show that in contrast to the subjects with sAD, the synaptic branches are practically normal in the elderly subject
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.
It is difficult to summarise the somewhat disjointed information in this section that tries to explain the complex development of the brain in infancy. But it is worth insisting that the first years of infancy and youth are instrumental in establishing the cognitive reserve (maternal care, food, absence of neurotoxins, the familial and school environment, and education are important for its development). Furthermore, at this age, a metabolic phenotype is established, which when the environment is adverse (mal/hyper-nutrition, genetic or epigenetic RF), makes some complex diseases more likely in the future, above all those of vascular risk
(obesity, diabetes, HBP, heart disease), and those of other kinds: asthma, osteoporosis, and there is more and more evidence that dementia and sAD are part of this set of complex diseases
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.
Another interesting aspect of this period of infancy/youth is the development of lifestyle, which is relevant to health. At the end of childhood and in adolescence the most rational guides to lifestyle are established, perhaps associated with a small peak in brain growth which occurs in adolescence. And in this context of life development, one of the greatest biological achievements of humans is important: the improvement in efficiency of the frontal lobe
( prefrontal areas), which integrates emotional functions and behavioural control. In this period many attitudes to health are formed which will be maintained during adulthood
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.
To finish off, table 12 (22c.1) gives a summary of the RF and PF, which are established in this initial period of life. In brief, to paraphrase a WHO memo: “in this period of life the health capital is established for the whole of life”. And we can add, specifically for brain health: and this why the prevention of Alzheimer’s must start from infancy.
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The Aberdeen and Edinburgh cohorts (Lothian Birth Cohort -LBC) are a unique. It comes from the Scottish
Council for Research in Education , and were for the evaluation of student cognitive performance. Cognitive tests performed on those born in 1921. In the last two decades, two elderly cohorts have been formed with the participants that agreed to be evaluated again ( Deary et al, 2004 ). Several publications, whose leaders are Ian
Deary (LBC) and Lawrence Whalley (Aberdeen) have generated more than 200 Medline articles, showing that low intelligence at 11 years was a RF of dementia and bad health in old age, and also, the importance of SES conditions in both ( Henstridge et al, 2015 ; Whalley, 2006, 2015 ).
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Tomalski & Johnson, 2010.
224
Blows, 1998 and Andersen SL, 2003 .
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Table 10 (22c.1). Risk factor for dementia and sAD in infancy and youth*
Maternal
FR ; Deficient nutritive and cognitive status, primiparity, stress, illnesses
FP : Breastfeeding, healthy life style
Familial and social
FR : Many familial offspring, low familial education, stress, low SES, poverty
FR : Environmental toxicity (metals, air pollution, pesticides and others)
FR : Bad personal and familial health (infections and others)
FP : High SES
Infant, children and youth
FR : Low cerebral development in the first two years (head volume, stunting), due to hyponutrition or other causes. Hypernutrition
Early alterations due to ambiance contact (verbal, light, other sensory stimuli)
Stunting and low corporal development
Low educations or intellectual achievement
Dyslexia or other language problems
Bad health (mainly cardiovascular)
Vital adversity episodes (father’s loss, sexual aggression and others)
FP : Adequate development and health. Intense physical exercise
Adolescence
FR : Low physical and mental exercise, obesity, toxic habits (tobacco, illicit drugs)
FP : Healthy and established habits and life style
*Synthetized from many authors; SES: socioeconomic status
22D. Does the risk of Alzheimer’s arise in adulthood?
If we were to be guided by the numerous published studies, analysing the start of the risk of
Alzheimer’s, we would have to say that the answer to the question in the title is yes. But it isn’t. As we have seen in the previous chapters, the risk comes earlier. Genes, family, the foetal period, childhood and adolescence are linked very clearly with the risk of dementia, sAD and other chronic illnesses that appear in adulthood and old age. Epidemiology over the whole course of life has subverted the studies of the previous decades which had mooted the importance of adult life in the genesis of the risk of the diseases of old age
225
, including dementia and sAD.
Figure 26 (22d.1) shows graphically what we have been saying throughout this monograph.
According to this figure adulthood would increase the pre-existing risks. This is a reasonable premise. Nevertheless, it is worth reviewing the numerous studies which stress that diverse
225
See Ben-Shlomo & Kuh, 2002 and Gluckman et al, 2006.
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risk factors (RF) and prevention factors (PF) of sAD might have their origin in adulthood, or rather, it has been detected in cohorts that they started in this period of life, although it seems reasonable that this judgement is biased due to the lack of studies of these factors in earlier periods
226
. All the same, these investigations into the RF/PF in adulthood have made it clear that these factors are previous to the dementias of old age.
Figure 26 (22d.1).
Risk dementia/AD factors evolution over the lifetime
The image represents the increase throughout life of risk factors for dementia that can initiate from the fetus (e.g., hyponutrition), continue in childhood (poor education), adolescence (CVRF, obesity) and adult life, and facilitate in the old age dementia/AD, if the pathological burden exceeds the cognitive reserve (CogR) of the individual
It is interesting to observe that the importance of environmental risk factor increases along the life and the genetic risk factor decrease. In some series, the APOE4 risk increase its effects from 50-75 years and then decrease in the old-old. Figure modified from Yankner et al, 2008.
The fact that there are countless studies of RF and PF in middle age leads us to mention only a few – the most outstanding. It must be stressed that most of the studies of RF in adulthood were carried out in the 40s and 50s and motivated by the epidemic of CVD in the US, and also in some northern European countries such as Finland
227
. The Framingham cohort has been mentioned – a paradigmatic example of the investigations in middle age
228
A very interesting study which is not discussed is the study of the Japanese who live in a US territory
– Honolulu in Hawaii. This study has the peculiarity that it was only performed on men. First it was called the Honolulu Heart Program and later Honolulu-Asia Aging Study (HAAS)
226
CVRF begin clinically in youth ( Brunner et al, 1999 ). The study performed in Sweden with young military personnel is paradigmatic. Good cardiovascular fitness status at 18 years was a PF for health in middle age (these soldiers were followed until 42 (mean 26 years). The cardiovascularly unfit personnel at 18 (measured by static bicycling with EKG recording) had worse health in adulthood and greater cognitive decline in early old age
( Nyberg et al, 2014 ).
227
228
Launer, 2005, and Reitz et al, 2011, review dementia and sAD RF in middle age.
In the aforementioned Framingham study, the first and second cohorts ( Elias et al, 1993, 2005 ; Linn et al,
1995; Satizabal et al, 2016 ) produced clear results: uncontrolled HBP during adulthood is an RF for CVD and dementia in old age; this cohort has such a large number of studies (more than 200) that is not possible to comment on the majority of them.
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when the cohort got older
229
.
The first part of the study served to demonstrate that environmental conditions are an RF of mortality from heart disease. How was it done? Well, with a complex investigation that showed how mortality from heart disease was lower in those who lived in Japan than in those who lived in California, with those living in Hawaii coming in between. These results demonstrated the environmental component of heart disease, as the genetic component was analogous (the participants were Japanese in the three areas), and thus the possibility of prevention of heart disease. The findings from the HAAS study in the area of dementia have been numerous. From a clinical perspective, HAAS makes clear the frequency of cases of mild dementia not noticed by the family, which confirms the need for population-based studies in this area (many cases are not spotted by the family and medical services). It also makes clear the importance of education and cardiovascular RF
(CVRF), including smoking, in middle age in the genesis of dementia in old age. But perhaps the most striking findings are the pathological ones (this study had a post-mortem examination for those who died): HBP and CVRF not only cause vascular lesions in the brain, they also increase the clinical manifestations of AD-type lesions. They have also shown that the brain lesions associated with dementia are much more varied than vascular and AD-type.
Let’s go to Europe, and then we’ll come back to Japan. That’s what literature allows – sudden changes of continent in this space of one line
230
.
In North Karelia , Finland
231
, a cohort of adults was established in 1972, 1977, 1982 and 1987 to study the RF of ischemic heart disease (the CVD problems mentioned in section 22a). The study was included in the multi-location WHO investigation, MONICA, which analysed
CVRF in many countries (in Finland it was called FINMONICA). The Finnish participants who were still alive at the end of 1997 (aged 65-79) and agreed to take part, lived in two geographical areas close to the city of Kuopio and numbered 1,449. Interesting results? There were no great surprises: the participants who had suffered from HBP and high levels of cholesterol (or both) had a greater risk of suffering from sAD in old age – similar results to those found on the other side of the Atlantic. The Finnish study has continued to follow its aged cohort to the present day, with another name (CAIDE)
232
.
Let’s make a quick journey back to Japan, to study the RF of dementia and sAD of the
Japanese in middle age. Although there are several studies in this country, we are only going
229
Honolulu Heart Program was initiated in 1991, and ended in 2012. When this cohort aged, the name was changed to Honolulu-Asia Aging Study –HAAS. HAAS had many publications. We highlight: the silent dementia presentation ( Ross et al, 1997 ); tobacco use that increased dementia risk ( Galanis et al, 1997 ); high cognitive performance is an elderly dementia PF ( White et al, 2010 ); the pathological studies show the consequences of HBP ( Petrovitch et al, 2000 ); and also, the diversity of lesions in senile dementia ( White et al,
2005 ). Its main pathological findings in dementia and sAD ( Gelber et al, 2012 ) included hippocampal sclerosis, cerebral atrophy, vascular microinfarcts, and demyelination of white matter. In the elderly, hippocampal sclerosis, sAD and other NDD, the genetic defects of the TDP-43 protein have a role ( Forman et al, 2007 ;
Josephs et al, 1015 ).
230
It is the advantage of thinking, it is faster than the teletransportation of Star Trek and light, with permission of
Einstein, naturally.
231
Vartiainen et al, 1997 , described the Finish cohort FINMONICA , and its dementia and sAD findings
Kivipelto et al, 2001, 2002 .
232
FINMONICA changed its name to CAIDE ( Cardiovascular Risk Factors, Aging and Dementia ). Its last review was performed in 2005-8 (total follow-up: 30 years), Vuorinen et al, 2015 . One interesting achievement of this cohort is to design an adult CVRF that established the probability of elderly dementia, analogous to the
Framingham index ( Kaffashian et al, 2013 ).
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to focus on the study performed in one city – Hisayama
233
. In 1961 a cohort was established in this small city of participants who from 1985 were examined every 6-7 years until 2012 to detect dementia. The whole population was invited to donate their brains after death and this invitation was taken up by 75% of those who died. The main clinical findings were fairly similar to those mentioned except that HBP was a clear RF of VaD, but not sAD. This fact can be explained by the high prevalence of vascular lesions in those Japanese who suffered from dementia (they suffer many silent strokes). In fact, until 2004, the most frequent cause of senile dementia in this study was VaD – the opposite of what is found in the West. Also, being poorly educated or a smoker proved to be clear RF of dementia, with moderate physical activity being a PF, above all for sAD. Perhaps the most striking findings of the Hisayama study are the nutritional results: a diet rich in soy and soy products, vegetables (including seaweed), fruit, milk and dairy products, and low in rice turned out to be a PF of dementia and sAD.
Are there more cohorts that study the RF of dementia and sAD in adulthood? Well, there are many more, but not as well-known, though interesting, and we shall just mention some very relevant ones. The outstanding study of 10,318 middle-aged British civil servants (aged 35-
50) who were followed for 17 years (the Whitehall II cohort) highlighted the importance of lifestyle: education, not smoking, exercise, and diet to reaching a healthy old age
234
. The
Swedish Uppsala
235
study showed that participating in social activities is a PF for dementia.
After referring to a Swedish study, we must mention the identical twin study (a very
Scandinavian subject)
236
. The studies of twins from early ages and other case-control studies have emphasised the relevance of RF in middle age to the development of dementia and NDD
237
. These studies have shown that certain cognitive features (e.g. reaction time) and even brain structures have important consequences, but in cognitive decline, dementia and sAD, environmental factors and cognitive level in middle age are very important.
In brief, the findings from these cohorts that have studied the RF/PF in middle age confirm the importance of: education, ApoE4 and CVRF. Of these CVRF, the most firmly established
233
The pathological investigation of the Hisayama cohort had some relevance. Honda et al, 2016, uncovered multiple types of pathology in its elderly dementia cases with, and maintain a “tauopathy” increase in the very old, probably associated with the westernisation of Japanese lifestyle. Crary et al, 2014, and Jellinger et al, 2015, also described an analogous tauopathy that they call PART (Primary age-related tauopathy) ), that has generated a vivid controversy with peculiar acronyms, SNAD ( Suspected non-Alzheimer disease , Jack et al, 2016 ) and
CART ( Nelson et al, 2016 ).
HBP ( Ninomiya et al, 2001 ) and being a smoker are RF for elderly dementia ( Ohara et al, 2014 ). In this survey milk intake is a PF for dementia and sAD ( Yamada et al, 2013; Ozawa et al, 2013, 2014).
234
See Marmot et al, 1991 and Britton et al, 2008. The Whitehall II survey shows that adult CVRF begin during childhood and youth ( Brunner et al, 1999 ).
235
The Uppsala Longitudinal Study of Adult Men Cohort (Franzon et al, 2015), is a prospective survey with a follow-up over more than 40 years in 2,293 participants and emphasizes the importance of not smoking and being fit to achieve a healthy old age without dementia. There are other Swedish surveys of high quality such as the Kungsholmen Project ( Fratiglioni et al, 2007 ) that indicate the importance of the HBP control in adults and eldery people in health and dementia prevention and, also, the social engagement.
236
The majority of twin studies have been carried out in Scandinavian countries, showing the relevance of CVRF in middle age for cognitive decline and dementia (FN # 101). In summary, in old age the genetic factors declined
(including ApoE4) during aging and the importance of environmental factors increases. The review of eight twin studies demonstrated these findings ( Lee & Sachdev, 2014 ).
237
The case-control study ( Friedland et al, 2001 ) shows that the patients suffering from sAD had less cognitive endowment and physical and intellectual activity during middle age than controls.
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are: increased BMI (obesity), HBP and DM2 (although there is less evidence), being a smoker, and obviously, having suffered a stroke or heart disease. Table 13 (22d.1).
Table 11 (22d.1). Risk and protection factors for dementia and sAD during adulthood
Previous commented factors
RF : ApoE4
RF or PF : Education (Cognitive reserve) and type of work or profession
CVRF
Obesity
HBP
DM2
To be smoker (or to other illicit drugs)
Others (stroke, cardiopathy, others systemic diseases)
Life style
FP : Healthy diet, moderate alcohol consumption?
FP : Intense physical and social activities
Abbreviations: RF: Risk factors; PF: Protection factors; CVRF: Cardiovascular risk factors
Also, diet has been shown to be important in some studies that have evaluated it (Hisayama).
In order to specify which aspects of diet, we must turn to the sub-studies of the cohorts or specific studies (CAIDE, PREDIMED). The same is true for other aspects of lifestyle (alcohol consumption, type of physical or work activity), which are analysed in specific reviews
238 and will be discussed in chapter 23.
22E. Don’t ignore old age
In old age the studies and investigations on dementia and Alzheimer’s (sAD) are simply innumerable and cover many very varied risk factors (RF) and protection factors (PF). Their methods are also varied: clinical, case-control , and numerous population-based cohorts. Faced with the avalanche of data we can only adopt a very selective attitude, thus committing undesirable omissions, but allowing a panoramic view of the existing studies
239
. Following this criterion, a brief description of the selected studies has been preferred to an inclusive summary, which makes it more difficult to read, but shows how the panoply of studies does not allow a simple summary, because in many studies they evaluate elderly people (65 and over) or people over 75-85 but the RF/PF often relate to earlier periods of life.
Let’s start with Europe and with the most important studies. There is no doubt that the
Rotterdam study
240
is the largest, not just for its analysis of dementia but also because it
238
The Hisayama cohort has important findings in this field ( Ozawa et al, 2013, 2014 ), analogous to the CAIDE
( Vuorinen et al, 2015 ), and the Spanish PREDIMED (see Chap # 23e).
239
The NEDICES monograph describes a summarised review of the main population-based surveys of ageing, dementia and AD and other NDD ( Bermejo FP et al, 2007).
240
The Rotterdam study is an investigation from the Dpt. of Epidemiology of the Erasmus U. in Rotterdam. Its principal investigator is Albert Hofman, a brilliant epidemiologist and lecturer that repeatedly visited Spain,
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includes several diseases: neurological, cardiovascular, of the eye (retinal degeneration, glaucoma), of the skeleton (osteoporosis) and systemic (diabetes). Its design and execution are magnificent, and it has generated a huge number of articles, which are of high quality in all the subjects of the study (more than 1,000 Medline publications), many on strokes, dementia and sAD. It has highlighted the importance of cardiovascular RF (CVRF) in the genesis of dementia, sAD and senile depression. High blood pressure (HBP) shows a complex association with the risk of sAD: it is associated with dementia until the age of 80, but not over this age, and it is also associated with lesions to subcortical white matter . Being a smoker doubles the risk of dementia and drinking moderately reduces it. Anyway, its main message is that prevention of dementia and sAD is a necessary action which includes acting on the CVRF; oxidative stress and inflammation are metabolic aspects in AD that should be prevented. It detected a gene in the retinal degeneration of elderly people.
Another outstanding European study is the British “Cognitive Function and Aging Study”
(CFAS)
241
. It is a complex study that has analysed three populations (Cambridgeshire,
Newcastle and Nottingham) at two times: the CFAS I, with a total of 7,635 elderly people from 1989-1994 and the CFAS II, which analysed 7,796 elderly people between 2008 and
2011. The methods of the study (sample selection, screening and diagnosis) were similar in the two studies and the findings have shown a lower prevalence and incidence of dementia in the second period, which indicates, along with recent data from the Framingham study and others that the incidence of dementia is decreasing in developed countries and that the prevalence is stabilising in these countries. The neuropathological findings are also important
– they have brought into question the 20 th
century concepts of dementia and sAD, as this study included brain necropsy of the participants who donated their brains, which were analysed by neuropathologists without seeing the clinical data. The observations can be considered “neuropathological epidemiology”, which differs from those that come from hospitals (the pathological basis in the 20 th
century) on sAD. In this study and other population-based pathological studies, it has been made clear that what is diagnosed as sAD is a heterogeneous pathological entity: in 75-80% of cases, mixed brain lesions (vascular, ADtype and others) are present – there are very few pure cases of either vascular dementia
(VaD), sAD, or other dementias. See figure 27 (22e.1). Its researchers have likewise invited by SEN and Areces Foundation. He performed the main European population-based survey in elders. The baseline survey included people aged 55 and over (7,983 participants) in 1990, but the population has increased several times, and since 2016, the cohort is being expanded by persons aged 40 years and over ( Ikram et al,
2015, 2017 ). This survey has neuroimaging information ( Rotterdam Scan Study ), biobank (with genetic analyses), and prevention sub-studies ( de Bruijn et al, 2015 ). Summarised findings in Hofman et al, 2006, 2008.
The number of Medline articles at the beginning of 2016 was greater than 1,500 (see www. erasmusepidemiology.nl/rotterdamstudy), and more than one hundred discussed clinical or genetic AD aspects.
241
The Cognitive Function and Ageing Study (CFAS), sponsored by the British Medical Research Council
(MRC), has carried out a huge elderly survey in England and Wales. This elderly survey based on medical lists began in 1989. This survey contributed to the dementia and AD field with important findings in clinical and pathological aspects (it had brain donation) ( Matthews et al, 2009, 2013, 2016 ). In the brains it investigated the dementia RF: ageing (18%), small brain (12%), NFD (11%), neocortical SP (8%), microvasculopathy (12%), multiple vascular pathology (9%), hippocampal atrophy (10%), amyloid angiopathy (7%) and Lewy body (3%)
( Mathews et al, 2013 ), stressing that the dementia pathology in the old-old is multiple like other studies (Zaccai et al, 2006; Schneider JA et al, 2007, 2009) . Carol Brayne, one of this study leaders and professor of epidemiology at Cambridge U. published more than 300 papers on this dementia and AD field. In an interview for Dementia (London ) ( Katz & Peters, 2013 ) she was very critical of the current concepts of MCI and AD, with biomarkers as predictors of sAD, and with the trials in selected (hospital-based) patients. She called for preventive population-based dementia and AD trials.
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highlighted the importance of prevention of dementia and sAD from the population-based perspective.
Figure 27 (22.e1).
Cerebral pathology in dementias in relationship to age
Schematic showing various pathological lesions in the brains of patients with dementia throughout aging. This figure specifies its presence according to different periods of aging. Vascular lesions
(CVD) that grow almost exponentially from the age of 50, are represented in a network with parallel lines and a continuous line. In a network of perpendicular lines, the pathological burden of type sAD lesions that can begin in childhood and possibly decline towards 90 years are shown in dotted lines.
On a gray background, cases of dementia without known pathology are represented. With small moles, several neurodegenerative lesions (ND) are exhibited: LBD, FTD, TDP-43, cortical atrophy and others. In large moles are depicted the sclerosis of the hippocampus (HS) that becomes very prevalent from the 80-85 years. Modified by Nelson et al, 2010, 2011 with data from other authors
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Figure 28 (22.e2).
Study areas of NEDICES cohort
Diagram of the NEDICES study sites. Arevalo county in Ávila province (rural area integrated by with
38 little villages); Getafe suburb, Margaritas neighbourhood (blue-collar workers), Salamanca district, Lista, area (Central Madrid, white-collar workers).
Let’s cross the Atlantic. In the US and Canada numerous large studies have been carried out on ageing and its main diseases. One of these ( EPESE ), sponsored by the NIA , analysed four elderly cohorts in four different parts of the country and obtained numerous data on the diseases associated with ageing, including dementia. Later it widened its population base to
Hispanics (elderly Mexicans) – the Hispanic ESEPE
242
. There are many other investigations
– too many to list. We shall cite a few: the studies of the universities of Duke, Columbia in
New York, and those of Seattle, Chicago and the 90+ study of California – very relevant and having neuropathological data; the Memory and Health Study of Cache County showed the importance of lifestyle to the development of dementia, and the decline of AD-type pathology after the 90s; and the Monongahela Valley Independent Elders Survey has contributed data on
MCI, dementia and mortality
243
. The Canadian CHSA deserves special mention, due to its
242
Established Populations for Epidemiologic Studies of the Elderly, a study sponsored by the National Institute on Aging (NIA) from NIH investigated the elderly health status in four population (Cornoni-Huntley et al, 1986 ).
One of its investigators, Robert Wallace, maintained the possibility of dementia prevention and the need for more studies in this field ( Haan & Wallace, 2004 ).This survey has also been performed in Hispanic background populations ( Espino et al, 1996).
243
The multiple surveys performed in USA in this field only permit a restricted comment on those with some peculiarities. The Cache County survey evaluated a population with high survival and special lifestyle characteristics ( Tschanz et al, 2005, 2013); the Monongahela Valley study has an excellent MCI and dementia mortality study ( Ganguli et al, 2005, 2011) . The 90+ analysed the dementia pathology in the very old-old
( Corrada et al, 2010 ). The population surveys of Chicago ( Bennett et al, 2014) and Columbia U. have been mentioned (e.g., Scarmeas et al, 2009 a); two of their investigators , ED Louis and Y Stern have collaborated in the NEDICES publications.
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size, methods and results. Besides, it has created a very precise pre-dementia entity: cognitive impairment no dementia (CIND) in the scientific literature
244
. All of these studies have discovered points of interest in the RF and PF of dementia and sAD in old age.
Let’s move stealthily through the studies in Latin America, Africa and Asia, noting that they too are numerous and that some RF and PF of dementia and AD have originated from these areas. The Shanghai study guided by Robert Katzman stands out, which showed that illiteracy was an important RF for dementia, by demonstrating that Chinese women (mainly illiterate at the time) suffered many more dementias than literate ones
245
. The study of the Afro-
American citizens of Indianapolis, some with Nigerian ancestors, compared with the Yoruba of Nigeria has produced some interesting findings
246
: the prevalence and incidence of AD is greater in the Afro-Americans than in the Nigerian Yoruba, which would indicate the importance of environmental factors in the genesis of AD. (The footnote tells the exciting story of the Indianapolis-Ibadan Dementia Project). A biologically relevant fact is that the genotype ApoE4 is not an RF of dementia in the Nigerian Yoruba.
We shan’t stop in Australia, where there are also some interesting studies, but return to
Europe to look at two studies on elderly people in France and Spain. Both investigations have a common feature in that they were led by neurologists, as opposed to the aforementioned studies, which were overseen by epidemiology departments. Let’s start with the older French study.
The PAQUID study
247 is an investigation of elderly people (3,777 people of 65 and over who lived in their homes). This sample was randomly generated from the 75 communities of
Gironde and Dordogne (south-east France). These participants were followed over more than
20 years; during this period over 800 people developed incident dementia and 2,500 died.
This long-term cohort has generated many publications related to psychometric and functional tests that predict dementia years before its appearance. It has also given rise to studies of RF for dementia and sAD with relevant results: demographic (never having married, the
244
The Canadian Study of Health and Aging is one of the largest population based study of dementia in one country in the world (second in size after Russia). It obtained a random sample of the entire population of the country ( Anonymous, 1996, 2000 ). It established a new concept of the predementia state: cognitive impairment not dementia (CIND) from population-based roots ( Jacova et al, 2008 ).
245
Two decades ago, the most frequent dementia in Asia (Japan and China) was VaD, but after the change to the western type of nutrition it is sAD ( Jorm, 1990 and Wu YT et al, 2015, 2016 ). The Shanghai survey ( Zhang et al,
1990 ; Katzman, 1993 ) is very relevant.
246
A Nigerian neurologist ( Osuntokun et al, 1992 ) detected that AD in Nigerians with Yoruba ethnicity was very rare. This finding originated a survey to compare this data with the Afro-Americans, this author heard in the
WHO debate – Age Associated Dementia-SPRA- that the majority of Indianapolis Afro-Americans participants were of Nigerian origin (but this fact was not reflected in the publications). This was a difficult investigation – the Yoruba had no age-registration and there are difficulties in interviewing in a forest area. The psychiatrists of
Indianapolis U. were the leaders of this survey ( Indianapolis-Ibadan Dementia Project) and they detected clear differences in dementia and AD prevalence and incidence (lower in Nigeria). This difference was attributed to environmental RF (diet and lower HBP and DM2 in the Yoruba), and genetic ApoE4 is not an RF in the Yoruba
( Hendrie et al, 1995, 2001) . Surprisingly, in 2016, a decrease in dementia incidence in Afro-Americans and not in the Yoruba was described ( Gao et al, 2016 ), which could indicate, now, better CVRF control in Afro-
Americans.
247
The French PAQUID survey (Dartigues et al, 1991) has generated more than 130 Medline publications. It had described many RF or associations with dementia: dietary antioxidants ( Helmer et al, 2003); ginkgo biloba therapy ( Amieva et al, 2013); education ( Amieva et al, 2014) ; air pollution ( Lepeule et al, 2006) ; PF such as wine ( Orgogozo et al, 1997 ) ; and social contact (Marioni et al, 2015) . The PAQUID survey has been followed by the Three-City (3C) survey (Alpérovitch et al, 2002 ).
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importance of professional training in youth); environmental (air pollution); nutritional
(ingestion of antioxidants, vitamin E and ginkgo biloba); and also genetic.
And finally, the Spanish NEDICES cohort, which has studied several neurological diseases
(in addition to dementia, MCI and sAD) and has data on mortality and its causes obtained from official registers. The study originated from a WHO project that aimed to perform a study with common methods (dementia screening and diagnosis with uniform tests and criteria) in six countries: Canada, Chile, Spain, the US, Malta and Nigeria, with the coordinating centre run by Professor Amaducci of Florence. The project did not succeed in enlisting the participation of the six countries – the US and Nigeria established their own study (Ibadan-Indianapolis), as did Canada: CHSA (both mentioned previously). Malta, Chile and Spain performed a study with uniform dementia screening by means of a 37-point
MMSE, suitable for populations of low educational level, and uniform diagnostic criteria.
Only Spain managed to carry the study out, through NEDICES, investigating neurological diseases and general health (the neurological diseases found in the elderly included in
EPESE). At baseline (1994-5), 5,278 elderly people were screened, from three geographical areas: a rural region (38 villages in Arévalo, Ávila), a blue-collar area (Margaritas in Getafe) and a white-collar area (Lista in the centre of Madrid). See figure 28 (22e.2). The study has analysed the mortality of the cohort until 2008 and is still publishing its data. The main findings: a) the RF for dementia and sAD detected: chronological age, low level of education
(and illiteracy), vascular RF (HBP, diabetes, smoking, suffering heart disease or stroke), and bad health. Physical activity is a PF; being a woman or suffering from previous depression are not RF (they are in some studies), but having lived in a rural environment in youth is an RF
(like in PAQUID). Well-treated HBP in the elderly person does not carry a risk of dementia at this age. The study has published results on Parkinson’s, stroke and essential tremor (few cohorts have investigated this) which is associated with a slight risk of dementia (a finding not previously described), and data on health and dementia in 90 nonagenarians of the cohort. Its lack of biological data led to a new cohort, NEDICES-2, with a bank of biological data associated. In Spain, numerous studies detected the prevalence of dementia in elderly people
(too many to mention). One that stands out is the ZARADEMP cohort (a study performed in
Zaragoza), which analysed depression and dementia over two decades and has shown a decrease in the prevalence of dementia in the most recent decade, even though this decrease is only clear for men
248249
.
248
The NEDICES ( Neurological Disorders in Central Spain ) cohort came from WHO: AAD-SPRA (Amaducci et al, 1991 ); it was established to perform transcultural dementia surveys in six countries. The AAD-SPRA team validated the common screening protocol and the diagnostic concordance of investigators ( Baldereschi et al,
1994 a, b ). AAD-SPRA promoted in Spain the EPICARDIAN ( Gabriel et al, 1999 ) and NEDICES surveys
(5,278 participants). NEDICES had many publications: a preliminary survey ( Bermejo, 1993 ). Methods:
Bermejo et al, 2001; Morales et al, 2004 ); its psychometric test: MMSE-37 ( Prieto et al, 2012; Serna et al,
2015; Contador et al, 2015 b ); and many MCI and dementia findings: memory loss ( Olazarán et al, 2004 ;
Villarejo et al, 2011 b); MCI evolution (Bermejo-Pareja et al, 2016 a). The NEDICES cohort data of dementia, and AD prevalence, incidence and main RF was described ( Bermejo-Pareja et al, 2008 a, b, 2009 a), also specific RF ( Benito León et al, 2009, 2010, 2013, 2014 ). In addition, its relationship with depression ( Olazarán et al, 2013 ), behavioral dysfunctions ( de Toledo et al, 2004 ); mortality ( Villarejo et al, 2011 a ); dementia in nonagenarians (Carrillo-Alcalá & Bermejo-Pareja, 2008) and dementia care-giver problems (Bermejo et al,
20024 ; Rivera-Navarro et al, 2008 ). NEDICES investigated other NDD disorders PD, essential tremor ( Benito-
León et al, 2004, 2005 ; Bermejo-Pareja , 2007, 2011; Sánchez-Ferro et al, 2013 a ) and its mortality ( Posada et al, 2011 ) because NEDICES has a link with the Spanish Official Death Registry. This survey detected a minimally higher risk of dementia in essential tremor patients ( Bermejo-Pareja et al, 2008), confirmed in a
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To sum up, in old age, CVRF are of primary importance in the appearance of dementia, although comorbidity (frailty) is a factor to take into account, and previous education is important as an RF/PF. Cognitive reserve can be increased in old age with a lifestyle that is cognitively and socially active, and physical exercise remains important. A low level of education, physical inactivity and social isolation are RF. An adequate diet and social integration (activity in the community, active leisure and artistic or religious activities) would be PF, although more studies are needed to prove this definitively. (A summary table is not given because it is analogous to table 13 (22d.1), although obesity (not extreme) is not an RF in old age, and excessive thinness is an RF.
Columbia (NY) cohort (Thawani et al, 2009). Other aspects of this cohort ( Sánchez-Ferro et al, 2015; Benito-
León et al, 2010, 2015; Gómez et al, 2015) and its attrition ( Vega et al, 2010) have been published . It is clear in
NEDICES that HBP control is a PF of dementia ( Bermejo-Pareja et al, 2013. (All studies are found in www.ciberned.es). NEDICES is finished but a new NEDICES-2 cohort with an associated biobank is ongoing.
249
The ZARADEMP survey (whose leader is Antonio Lobo, professor of Psychiatry in Zaragosa) has detected a decrease of dementia prevalence in the first decade of the 21st century versus the previous decade in men ( Lobo et al, 1995, 2007 ).
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This chapter analyses the modifiable risk and protection factors (RF/PF) in sporadic
Alzheimer’s (sAD) and dementia (many studies do not separate them), their plausibility and biological basis. Also, recommendations are made in order to suppress or maintain them
250
.
The recommendations are based on “scientific” common sense, since although they are not based on falsifiable studies (verifiable, such as trials), they are supported by sufficient proof from the population-based perspective. They have been arranged in several sections and the literature has been summarised with systematic reviews and meta-analysis . Also described are the recommendations of experts or of clinical guidelines that have the consensus of authors.
Before describing the RF/PF, it is worth mentioning three technical points: a) apart from ageing, which is a consistent and high RF, the rest of these factors have a low relative risk
(RR) (the risk of each factor is little over one or two (>1-2), which contrasts with other neurological pathologies, whose risks are higher (e.g., HBP has an RR of 3-4 for strokes).
Chronological age, however, carries a high risk: the prevalence of dementia doubles every five years from the age of 60-65 and its incidence in those over 85-90 could be 20-35 times greater the incidence at 60-65 (RR of 20-35); b) the genetic risk is not analysed (it is not modifiable now, although perhaps it will be in the future). According to identical twin studies, it could oscillate around 50% for sAD ( figure 15
-10.1), although it must be borne in mind that the risks vary for each person and age at which sAD appears; c) most systematic reviews make clear the heterogeneity and multiplicity of the RF/PF. Table
14 (23.1) shows the main individual modifiable RF/PF of a large and recent systematic review and meta-analysis of Alzheimer’s
251
.
Table 15 (23.2)
252
serves to better explain the importance of these RF in the population (PAR).
In its action paper for the period 2017-2025, WHO considers that dementia risk reduction is a necessity. The Draft WHO global action plan, 2016, stated “ There is a growing consensus that some protective measures might reduce the risk of cognitive decline – specifically, there
250
In its action paper for the period 2017-2025, WHO considers that dementia risk reduction is a necessity. The
Draft WHO global action plan, 2016, stated “ There is a growing consensus that some protective measures might reduce the risk of cognitive decline – specifically, there is some evidence that physical activity, early-life educational opportunities, management of midlife hypertension, tobacco cessation and a reduction in obesity and diabetes may reduce the risk of cognitive decline ”.
251
Fratiglioni et al, 2000, shows the extraordinary increase in the dementia incidence with ageing in a pool of
European surveys. X u W et al, 2015 a, review the risk and protection factors in population and case-control surveys and quantified the intensity of associations according to the number of participants (5,000 or more) and with a heterogeneity index; its comprehension needs focused attention.
252
Table 15 (23.2) describes the RF/PF from the population perspective (including dementia and sAD). This table’s data came from several authors. The population attibutable risk (PAR) , indicates the percentage of illness attributable to a specific RF in the population. Individual relative risk (RR) is different to its PAR because in the population similar individual risks could have very different quantity (prevalence) at population level. For example, being a smoker has greater PAR than suffering from DM2 because independently of its RR, in the population, being a smoker is very much more frequent than having DM2. In the population, the greater PAR of dementia could be due to low education (19-24%). (Obviously not all people suffer from all risks listed in the table, for that reason, these risks could be greater than about 50% attributed to environmental risk factors in sAD); the other RF could be genetic, although, Xu W et al, 2015, stated that 66% of dementia RF will be environmental (OR, RR, and PAR are described in the Glossary ). Recently, a calculation of reduction of AD and
VaD in Europe and Italy by the reduction of PAR is published ( Mayer, et al, 2018 ).
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is some evidence that physical activity, early-life educational opportunities, management of midlife hypertension, tobacco cessation and a reduction in obesity and diabetes may reduce the risk of cognitive decline ”.
Table 12 (23.1).
Modifiable RF and PF for Alzheimer disease #
Heavy smoking & 2.0
Current smoking in Asians 1.7
Carotid atherosclerosis 1.6
Healthy diet 0.45
High folate intake
Current statin use
0.5
0.52
Low education 1.3
High homocysteine (blood) 1.2
Ever use of oestrogen
Alcoholic drinks *
0.62
0.6
1.1
$ ȕ EORRGLQGH[
Systolic high pressure (>160)1.1 Fish ingestion
0.68
0.7
# Selected from Xu W et al, 2015 a
+ Mean RR, without CI
& > 55.5-156 pack-years.
*Mild-moderate (<4 drinks/day); ** ever use
Abbreviations: RR: Relative risk; OR: Odds ratio (see Glossary or Riffenburgh, 2006)
BMI: Body mass index; DM2: Diabetes mellitus type 2.
Commentary: all listed factors have fairly-adequate population based evidence, except the listed in italics (own appreciation).
Table 13 (23.2). Risk and protection factors for AD at population level. +
RF
Low education
Tobacco habit*
19-24% (less than primary school 40%)
13-31.1%
13%-31.22%
Depression 10%
HBP 5-8.99%
Obesity 2-3.4%
Diabetes (adult/older)
Comorbidity
2-8.4% (number higher in Asians)
2-3%***
4.9–27.3%
FP&
Healthy diet ?
21.9%
?
+ Own synthesis from data of many author, mainly Barnes & Jaffe, 2011 ; Anstey et al, 2013, 2015 ;
Beydoun et al, 2014, Deckers et al, 2014, Norton et al, 2014, Xu W et al, 2015; Livinsgtone et al, 2016
(data are not concordant , generally).
*Current smokers could have higher risk; ** Scarce PhA *** Co-morbidity calculated from NEDICES cohort. & Obviously, the inverse of RF are PF
&& More than one fish intake /week. See FN # 252
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23A. Ageing
In all of the studies, chronological age is a clear risk factor (RF) for dementia and
Alzheimer’s (sAD) until the age of 90 – after this age AD-type pathology might decrease, but the incidence of dementia continues to increase
253
. Be that as it may, ageing is a clear RF of dementia and sAD. And this is where the question arises: “Why? What is it about ageing that leads to this risk?”
It’s easy to define ageing by chronological age, but difficult from a clinical or biological perspective
254
. Years ago, when myocardial infarctions were very frequent, it was said that people were as old as their arteries. They don’t say it any more. So what is ageing? There are various stances. A famed Oxford epidemiologist, Peto
255
, wrote an often-cited provocative article: “ageing doesn’t exist and cancer is not related to it”. His thesis is that the carcinogenic effect of certain chemical compounds, when applied to experimental animals, is proportional to the third-fifth power of time (t
3
to t
5
) of exposure, but this effect does not depend on the age of the mice. So the duration of exposure would be to blame for experimental cancer and not the age (ageing) of the animals. In other words, he maintains that biological ageing is different from the diseases associated with it. This fits with the concept of biological ageing as the result of the imbalance that the environment causes to the normal physiological mechanisms – these must repair the biological errors which are suffered throughout life, and which must be corrected by the cells (or the organism). This repair is successful at the beginning and in the middle of life, but is more difficult to achieve in old age due to the accumulation of biological waste. As a consequence, a weakening would be produced – a decrease in the functional capacity of certain physiological processes. This concept is a position advanced in contrast with the previous stances that maintained that ageing was genetically programmed in the biological machinery of the cells
256
.
Let’s not look on the negative side – nowadays it is not believed that ageing is genetically determined in living beings. The proof of this is that their survival is very varied – from the
1400 years of the hydra to the 25 days of some worms; there are thousand-year-old trees, species of clam that live 500 years, whales over 250, and 200-year-old tortoises. It is even true that not all living beings experience an increase in mortality with increased age (e.g. for some desert tortoises, the older they get, the less likely they are to die). There is also a great variability in lifespan in each species (mice live much for a much shorter time in their natural
253
The dementia prevalence and incidence surveys ( Jorm, 1990, 1987, 1998 ) demonstrated this. Nelson et al,
2011 described how AD-type pathology decreased over 90 years (for this author this finding would be evidence that sAD is not accelerated aging). The situation is complex, it is true that the typical AD pathology decline in the oldest-old demented patients in relationship to younger AD demented ( Savva et al, 2009; Corrada et al,
2012). However, NFT persists increasing, possible in the form of PART ( Crary et al, 2014; Jellinger et al,
2015 ), and other lesions such as cortical atrophy and synapsis loss ( Terry, 2000 Terry & Katzman, 2001 ) .
Moreover, in population-based surveys the dementia incidence increases continuously ( Corrada et al, 2010,Yng et al, 2013) .
254
255
There are more perspectives: psychologists, sociologists… consult, Erber, 2013 ; pp: 8-10.
256
Peto et al, 1985, with experimental data; Peto & Doll, 1997 , with clinical data. FN # 146.
The continuous passing of time could generate stochastic or environmental biological alterations, which are difficult to eliminate. The field of aging theories is wide and complicated ( Kowald & Kirkwood, 2016 ). Blasco
& Salomone, 2016, wrote an interesting accessible monograph; in addition, there are many reviews, with biological background ( Ljubuncic & Reznick, 2009 ), sociological ( Hasworth & Cannon 2015 ), or from a biological systems standpoint ( Yankner et al, 2008 ; Bishop et al, 2010) .
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environment than in an environment without predators, in other words where there are no cats)
257
.
“Yes, but it’s not like that with humans”, it could be objected. Well, the limits of human survival are no longer that clear. Humans are living longer and longer and this is a scientifically proven fact. A German researcher from the Max Planck Institute of demographics performed a careful study from the 18 th
century (1750) in Sweden, where in many populations records from these times exist (birth certificates and parochial death registers) and showed that human survival has been increasing from those times until now
258
.
And the same is true of Spain, although the records are from later. And it has been calculated that the survival curve increases with a gradient of 0.23 per year lived (in the countries with high survival like Spain – two tenths below Japan)
259
. This is good news, which would indicate that for every five years lived, there could be an increase of a year and some months of life compared with the data from the past…
260
. The increase in human survival is a fact established not only by the aforementioned study – there is more proof: there are more and more centenarians (and super-centenarians – aged over 110), although none has passed the
French woman, Madame Calment, who lived to over 122. There is a lot of news about survival that is difficult to believe, but we aren’t going to go into science fiction
261
, or analyse the fashionable anti-ageing remedies, some of which are expensive and have very dubious results
262
. We don’t want to tread on dangerous ground – let’s stick to clear facts.
There are areas in the world called blue zones that are famous for having high numbers of centenarians and super-centenarians. And what do they have in common? Well, their inhabitants lead a life with a lot of physical exercise, a frugal diet abundant in fruit, vegetables and pulses, the absence of toxins (tobacco), good social interaction, without stress and in a benign climate (Icaria in Greece, Costa Rica, Okinawa in Japan…)
263
. The interesting story of the blue zones of the planet has been told in the media and we shan’t dwell on it here. But be warned: human survival depends largely on the environment – inheritance does not play a big role: perhaps only 25% of survival is due to genetic inheritance
264
. Another objective fact: the studies of healthy or successful ageing have brought up the issue of the importance
257
Jones OR et al, 2014, reviewed the survival in many different beings, a surprising article.
258
James W Vaupel is a demographer of exceptional talent, founder and director of the Max Planck Institute of
Demography in Rostock (Deutschland). His thesis is that the human survival has been increasing since 1750; from 1861, the registries in Sweden are exceptionally accurate ( Vaupel, 2010) FN # 10.
259
OECD, 2015, data demonstrated that the expected survival in Spain is 83.2 years, near the 83.4 of Japan
(world leader in life expectancy). The projections of the Spanish National Statistical Institute (INE), 2016, indicate that the birth survival expectancy will be 84.0 years in men and 88.7 in women by 2029; this signifies a gain, in relation to 2014, of 3.9 and 3.1 years respectively. In 2014, only Cypriots and Italians lived longer than
Spanish men; Swedish men live more or less the same, and Spanish women were second after Japanese women.
The age increase from 1910 to 2009 has been 4.8 months for each year of life in Spain.
260
261
Peto & Doll, 1997; Hofman et al, 2006, 2009.
This is what futurologists are for , Michio Kaku, 2014 , and Ray Kurzweil, 2012 , who state that people born after 2050 will not die…and he explained this incredible hypothesis.
262
Olshansky et al, 2004 analysed the now fashionable anti-aging remedies; not true in his opinion.
263
Blue zones have generated an extensive bibliography in (see in references, Wikipedia). In these blue zones, there is a high survival with many centenarians. The Nuoro province in Sardinia; Okinawa island in Japan;
Nicoya in Costa Rica; Icaria island in Greece, and Loma Linda in California. In Sardinia there is a mountainous area with many centenarians (men and women), without a clear explanation ( Poulain et al, 2004 ). There are many texts on Blue Zones (Dan Bruettner, 2008 ), reports: National Geographic , Newsweek , and a project to expand these areas to cities: Blue Zone Vitality (Willett & Underwood, 2010) .
264
This is the Vaupel, 2010 thesis, and Blasco & Salomone, 2016 commented on it.
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of health throughout life to achieving longevity, and the fact that a healthy old age is associated with little cognitive decline or dementia
265
. But since an explanation of the biological bases of the RF of dementia and sAD has been promised, we have to delve into a complex subject…well, it’s not really that difficult…
The interest in the biology of ageing has only really arisen in the last 2-3 decades – previously it was not considered that significant. Despite this lack of interest, the scientists who studied ageing in invertebrates started to come up with some significant findings. Firstly, that ageing is not immutable: in all species, it varies according to the environment. Secondly, the survival of invertebrates, flies and mice can be prolonged by altering the environment (e.g. with calorie restriction ). And thirdly, various biochemical modifications can prolong the lives of these experimental animals. These modifications seem to be manifold and are shown both in the expression of certain genes in the tissues of the aged animal and in the cellular metabolism . It is worth mentioning, due to the expectation that it generated, the discovery of a gene that prolonged life in mutant worms ( C. elegans ), which was called Age-1
266
. All these discoveries have encouraged an anti-ageing research movement, which is so important that the American Food and Drug Administration ( FDA ) has qualified its judgement that ageing is not a disease, allowing trials of drugs that act specifically against it. The discovery of possible therapeutic applications can be included in this area – there are several candidate drugs
(metformin, everolimus, rapamycin). There are even possible therapeutic avenues related to the discovery of human chromosomal telomeres (which shrink with age; measuring their length would be a way to calculate our biological age, forgetting about birthdays); there is an enzyme that impedes or delays this – telomerase – which could be pharmacologically modified to prolong human survival
267
. And there are more very interesting developments: the techniques of reprogramming of induced pluripotent stem cells , which can rejuvenate aged cells in vitro and in vivo and can turn back cellular ageing, could be of use in
Parkinson’s and sAD
268
. This is good news, and there will be more as science advances at a terrific pace.
“So are we close to the elixir of eternal youth?” All the postulates of almost-science-fiction get delayed, but here we are with drones, and the quantum computer is just around the
265
S uccessful aging is a concept of Rowe & Kahn, 1987 , also with success in the biomedical literature, although its definition is under debate ( Depp et al, 2014 ). There are data of its prevalence ( McLaughlin et al, 2010 ), and there is a concept derived from it: “successful cognitive aging” ( Daffner, 2010; Blazer et al, 2015 ). In
NEDICES baseline data, 15% of participants can be diagnosed as “ successful aging ”, with good cognition, health and less mortality ( Bermejo-Pareja et al, 2011 ). The concept of “positive aging” indicates that independent of their health, the elderly have a proactive and happy old age ( Erber, 2013 , pp: 391-2); Butler RN,
2008 ; pp: 383-94 maintains a similar concept in his very readable monograph.
266
The exciting story is narrated with suspense in the Blasco & Salomone, 2016 monograph. The little worm,
Caenorhabditis elegans, prolonged its life with biologic manipulations ( Kenyon, 2011 ).
267
The biological tissues that are associated with aging are multiple in the mouse, with an increase in free radicals (oxidative stress) and can be ameliorated with catalase enzyme treatment (its life can be prolonged by
20%; another anti-oxidant such as revesteratrol -contained in raisins- has similar effects, and there are many more…). Consult Blasco, 2013; Bär & Blasco, 2016 . To calculate the biological age there are markers: clinical, such as a gripping a dynamometer ( Sanderson & Scherbov, 2013 ), biological, genetic and epigenetic, but none of these has been validated yet.
268
T he techniques of reprogramming of induced pluripotent stem cells are close to science fiction , that is to say, pluripotent stem cells induced by Yamanaka (Japanese Nobel laureate) that permit the rejuvenation of any cell type and in the future could be an anti-aging therapy. Moreover, it could be a therapy for NDD (AD, PD) and other illness ( Soria-Vallés & Lopez-Ortín, 2016 ), see Glossary. Recently, this methodology has been applied in vivo in a mouse ( Ocampo et al, 2016 ).
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corner… The biological mechanisms of ageing encourage the appearance of NDD and sAD.
It’s not easy to explain why, as it isn’t clear. For systems biology , the biological doctrine that has come into medicine with the new millennium, ageing is a molecular process – a lack of biological repair that affects living beings and their cells. In practice it is believed that several of the mechanisms that are disrupted during senescence : deficit in the repair of nuclear and mitochondrial DNA, increased cellular oxidative stress, epigenetic dysfunctions in the expression of genes, mechanisms of neuronal signalling, etc. are responsible for ageing.
Recent studies show that factors related to the response to cellular stress and the modulation of genes that diminish the oxidative processes get hampered during ageing and sAD. In summary, the many metabolic pathways of the neurons are impaired during ageing and this encourages the appearance of sAD and other NDD, so pharmacological actions or environmental modifications that decreased senescence would increase the resistance to
Alzheimer’s. In other words, the actions that delay ageing in some way (lifestyle and future drugs) could prevent or delay the appearance of sAD
269
. And to support this thesis, there are clinical, epidemiological and molecular biology data that suggest this. ( Table 16 -23a.1).
Calorie restriction (and other possible drug therapies) don’t appear in this table. The reason for this is that calorie restriction has shown its efficacy in prolonging the life of animals including primates, even improving the cognitive performance of primates and humans, but it has not been demonstrated that it increases survival in humans. Don’t worry – there is already a study underway that is investigating this question (only 1,800 calories a day instead of the more than 2,500-3,000 of the average American). But questions still remain: “Which is better: continuous or intermittent calorie restriction? Primitive man went days without food.” And also, we have to be aware of a fact: calorie restriction in humans reduces libido (so now to the phrase “when you’re feeling bad the doctor takes away tobacco and alcohol…” we must add food and even sexual desire… all this for a longer life – well, it will certainly seem longer)
270
.
269
Several neuronal mechanisms have alterations during aging: synapses and neuronal plasticity as specific mechanisms in neurons. More general cellular mechanisms suffer alterations during aging, such as an increase of autophagy, less protein metabolism, deficit in insulin signals and TOR ( target of rapamycin ) mechanisms that determine inhibition of a protein related with the genes that facilitate cellular stress resistance; also, alterations in sirtuins (proteins related to the caloric restriction responses). Some cellular mechanisms evolved into up regulation such as genes associated to cellular stress (these are decreased in sAD). See Yankner et al, 2008;
Bishop et al, 2010 . Recently it has been found that the REST factor (see Glossary and Lu T et al, 2014), that protects neurons against oxidative stress is decreased in MCI, sAD and NDD; perhaps its activation could lead to new therapies in these disorders.
270
Mattson et al, 2014, 2015, describe this in detail in their surprising works. There are diets that demand total food abstinence (1-2 days/week) only to decrease calorie intake.
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Figure 29 (23a.1).
Elderly life expectations in Spain and its projection for the future*
According to Instituto Nacional de Estadística (INE) (Spanish National Statistical Institute)
English translation: [Evolución de la esperanza de vida al nacer] : Evolution of birth life expectancy .
[Años] : years; [Hombres] :Men ; [Mujeres] :Women
*Reproduced with permission.
To finish, just one recommendation: healthy ageing delays senescence and the appearance of sAD. During old age, having practices that encourage health (physical exercise, social and intellectual activity, healthy diet) can delay biological ageing and the appearance of sAD. We must achieve better health in order to achieve successful cognitive ageing, or at least
“positive”
271
cognitive ageing.
Table 14 (23a.1). Factors that promote cognitive successful aging*
Physical exercise + + + + + + + +
Cognitive stimulation + + + + + +
Cholesterol/Statins
G. biloba
Resveratrol
+ +
í
+ +
í
í
+ + +
í
í
+ + +
Anti-oxidants
í
+ + +
í
í
Healthy diet
Omega-3*
+ +
+
+
++
í
í
Modified from Daffner et al, 2010; * Decosahexaenoic acid (DHA )
271
There are many accessible texts like (e.g., Suzuki & Fitzpatrivk, 2015 ) to ameliorate cerebral health and antiaging (from physical exercise to meditation).
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23B. Education and cognitive reserve
After ageing, education is the most consistent risk factor (RF) or protection factor (PF) in dementia and Alzheimer’s (sAD), although this is not observed in all studies, in contrast with ageing because, among other reasons, education is a complex construct that does not mean the same thing in all cultures
272
.
Let’s do a bit of history. Although there were precedents, the first large study that proved the relationship between education and dementia was the investigation of prevalence of this disease, performed in Shanghai (China) by a Chinese team with the collaboration of a North
American expert (Robert Katzman, chapter 7). Carried out at the end of the 80s, it was one of the largest studies of dementia at the time, with over 5,000 participants. Among other findings, it showed that low level of education in the Chinese women of this investigation, mainly illiterate, was a clear RF for dementia
273
. Since then it has been evident that the absence of formal education is a clear RF of dementia, detectable in populations that at the start of the 20 th
century had high rates of illiteracy, such as in Spain. This effect has been made clear in the NEDICES cohort
274
as well as other Spanish and European studies, and in general, in populations worldwide where there is a wide range of educational level among the elderly people. It is a constant RF/PF in reviews on the subject, including systematic reviews, above all in developed countries but not such a clear RF/PF in developing countries
275
. These findings have appeared in population-based and case-control studies, and even in identical twin studies such as the Swedish HARMONY study (more than 20,000 twins followed for a long time)
276
. In brief, it seems clear that illiteracy and little formal education (above all less than 8 years) is an RF of dementia and sAD, but it is not clear what level of education has to be achieved in order for it not to be an RF or for it to be a PF.
“So what is clear is that not having an education means a risk of dementia but being very well-educated doesn’t protect against Alzheimer’s. Is it like that?”
272
Margaret Gatz, professor of Psychology and Gerontology in California U (Los Angeles) has analysed the relationship between education and dementia in her review in all geographical areas of the world. She demonstrated that education is a dementia RF ( Sharp & Gatz, 2011) . She was also the director of the Study of
Dementia in Swedish Twins .
273
Zhang et al, 1990; Katzman, 1993 .
274
Being illiterate and having a low level of education is an RF for dementia and sAD in the NEDICES cohort
( Bermejo-Pareja et al, 2008; Contador et al, 2015 a ) (Consult FN # 51) .
275
In Europe, analogous data were obtained (Letenneur et al, 2002). Bermejo et al, 2016, discusse this association and maintain that low education is associated, in the vast majority of surveys, with higher incidence of dementia and sAD in developed countries. In certain areas of USA, where the elderly had an adequate and uniform basic education at the beginning of the 20 th
century, such as Rochester, Minnesota ( Beard et al, 1993) or in the first Framingham cohort ( Cobb et al, 1995 ) this relationship does not appear. Nevertheless, in the
Framingham cohort over the last 30 years in which the incidence of dementia is clearly decreasing, the only factor that explained this finding is education ( Satizabal et al, 2016 ). In Spain, the majority of surveys detected this association ( de Pedro Cuesta et al, 2009 ); and in one meta-analysis ( Caamaño-Isorna et al, 2006) the conclusion was that low education is an RF for dementia and especially for AD . This finding is unanimously accepted in the reviews : Williams et al, 2010; Reitz et al, 2011; Barnes & Yaffe , 2011 ; Beydoun et al, 2014;
Imtiaz et al, 2014; Norton et al, 2014; Anstey et al, 2015; Whalley, 2015 ; Xu et al, 2015 a; and Wu et al, 2016.
See also Chap 7.
276
Gatz et al, 2007, demonstrated that the relationship between dementia and education is complex, and is modified by age, sex and race; it depends more on environmental factors associated to both than the genetic burden.
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Well, no, it isn’t like that, or it’s only partially like that. There is a systematic review that shows in no less than 47,028 people that being educated protects against dementia. But this study, more than education received when young, analyses the so-called cognitive trajectory
(childhood education, complexity of work, and intellectual activities in old age)
277
.
Let’s start at the beginning. Obviously, education begins in infancy. During the early postnatal period, above all in the first two years, and of course in the first 5-6 years, the majority of the brain is formed (over 90%), as has been described, and in these years education starts to act on the web of synaptic connections of the brain and this continues with formal education in early childhood. And this is where several questions arise. “And isn’t education in late childhood and youth important?” and “Do the cognitive skills acquired throughout life, like work, literary or artistic hobbies, travel and others that require intellectual effort also have an influence on the so-called cognitive reserve ?” Well, yes, they’re all important – a very well-studied example of the fact that greater education decreases the risk of dementia is the bilinguals that have less risk of dementia than those who only speak one language (who are similar in other features)
278
.
“But why education and cognitive reserve?”
Let’s start at the beginning again. Chapter 7 described what cognitive reserve is and chapter
22 explained the importance of the prenatal and early postnatal periods to the formation of the brain. Any stress or lesion during this critical period has, or can have, future consequences.
These consequences can pass unnoticed for a large part of life and manifest themselves in later years (when the physiological capacities are lesser) in the form of cognitive decline, dementia and sAD (these deficits increase the likelihood of these disorders). Also, we promised two things in this section: to analyse the biological bases of why education (and the more complex cognitive reserve (CogR)) can protect against dementia and sAD. Later we shall give some recommendations about this RF or PF (depending on how you look at it).
Since the 90s there have been data that indicate that better educated people have a larger synaptic network between their cortical neurons, and furthermore, with a dose effect (i.e. the more education the subject has, the greater his synaptic networks). It is not easy to verify these data in humans and not all the pathological studies confirm them. But there are sophisticated studies that do confirm them and that show peculiar pre-synaptic impairments related to education and CogR
279
. There are also biochemical and neuroimaging studies. In recent years these have increased in importance and they are very numerous, besides being performed with various techniques (CT, MRI, fMRI at rest and during the performance of various cognitive tasks, and PET scans). All of these have made it possible to analyse how a high or low level of education can modify the functioning of the brain. Given that the
277
This is the statement of the systematic reviews of Valenzuela & Sachdev, 2006 a, b . People with the highest cognitive trajectory throughout life have less than 46% dementia risk.
278
279
Consult Bialystok et al, 2016 as a summary of many studies.
Jacobs et al, 1993, described the synaptic modifications related to education. Honer et al, 2012, described an increase of synaptic proteins in people with high CogR and great AD burden that do not suffer from clinical AD
(these presynaptic proteins could be a biomarker of CogR). Perez-Nievas et al, 2013, also, described the synaptic and axonal aspects that differentiate people resistant to dementia. Franzmeier et al, 2018, by means of fMRI indicate that higher left frontal activity could be a marker of CogR. It is worth bearing in mind that education or
CogR are not associated with a decrease of the dementia pathological burden, only with its clinical appearance
( Bayne et al, 2010 ).
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description of these studies is complicated by the different techniques used, evaluation methods and populations evaluated, they won’t be described here, apart from with one sentence: people with a high level of education have more brain activation patterns in the neuroimaging studies
280
. To sum up, there is a biological correlate of how a high level of education translates into the functioning of the human brain, which is detectable through pathology and neuroimaging.
And if that wasn’t enough, studies in experimental animals confirm what has been observed in humans. In animals, education can be likened to what has been called cognitive enrichment
(keeping rats in environments in which, through changing games, mazes, wheels, etc., they learn where to find food and rewards – i.e. cognitive enrichment versus the solitude of a cage, even if they are kept with other rats). The results are similar to those found in humans – an increase in the cortical synaptic networks. This effect has been described in dogs, as in rats, and cognitive enrichment also protects them against senile cognitive deterioration
281
.
It is worth pointing out that some authors disagree with these results insofar as it is difficult to separate education from socioeconomic status (SES), or in other words, from childhood poverty and the consequent work disadvantages. And there are others who believe that education must be considered as learning throughout life. There is some truth in what both groups say. There is debate as to whether education is an RF/PF that can be isolated from other environmental aspects linked to education (SES and others)
282
. Also, there are paradigmatic examples of how having a specific profession can mould certain brain structures such as the hippocampus in adults (veteran London taxi drivers have a more developed posterior hippocampus than new drivers)
283
. Furthermore, there are examples that in elderly people, an active lifestyle, with intellectual hobbies and participation in cognitive training activities ( cognitive stimulation and stimulation of memory and other capacities improve the
CogR). And in healthy elderly people there is proof that the synaptic networks proliferate as if age was not a barrier to this biological development
284
. In favour of the position of education throughout life is the fact that education changes over the course of life (it can increase or decrease at various stages). And this is why, despite the importance of education in childhood and youth, intellectual training is a task to perform throughout life. A recent British study shows that formal education, intellectually stimulating work and social participation protect
280
Murray AD et al, 2011 ; Arenaza-Urquijo et al, 2013 , and Bozzali et al, 2015 analysed the neuroimaging studies and their relation with education and CogR.
281
282
See Milgram et al, 2006, in experimental studies (rodents and dogs). See also Chap # 7.
Education has many proxies: SES, poverty, work difficulty and others; nevertheless, several studies highlight the fact that that education and intelligence are factors that can act in an isolated way ( Karp et al, 2004 ). McGurn et al, 2008, comment that infant education has more relation with VaD than with AD, but this observation is not unanimous. My own opinion is in agreement with Margaret Gatz ( Sharp & Gatz, 2011) that maintains that education is a marker of familial and social atmosphere in clear relation with peri- and post-natal SES. Education has important repercussions in structural and functional brain capacity and determines Cog R. Luigi Amaducci, an excellent Italian epidemiologist repeats the same statements in many lectures and texts. Obviously, post-infant education is a process in which intelligence and many other factors throughout life have an influence.
283
A classic example is the findings in the London taxi-drivers: the number of years worked as a taxi-driver correlated positively with posterior hippocampus size (a brain structure related with spatial orientation and memory), Maguire, 2001 . Whalley, 2015, demonstrated that SES disadvantage in young people had a relation with a smaller hippocampus in the elderly. This astonishing subject is reviewed by Richards et al, 2003, 2005;
Sharp & Gatz, 2011; and Xu et al, 2015 a .
284
See Buell & Coleman, 1981 .
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against dementia
285
. To finish up, we should highlight the fact that better education is the only PF of dementia described in the reduction of incidence of dementia in the Framingham
Heart study and it only appeared in people with a secondary education
286
.
23D. Physical exercise is always required
The growing urbanisation, mechanisation and motorisation of the planet, a phenomenon that seems irreversible, has brought with it a decrease in physical activity (PhA) in humans, especially in developed countries due to the new forms of work (sedentary) and leisure
(digital technology and TV). This decrease in PA also affects children, whose decline in hours of physical exercise is remarkable. Most urban children watch 40 hours of TV a week, spend
25 hours sat in the classroom and 10 hours playing on digital devices. This phenomenon has been called “infant nintendoisation”
287
. Physical inactivity greatly affects urbanised and opulent societies.
Having abandoned the practices of primitive man, who needed continuous
288 physical effort to survive, seems to have consequences for intellectual performance, above all in senescence when physical and intellectual activity decrease physiologically. But not only in senescence: there are studies that show that excessive hours in front of the TV are associated with very little PhA in adults, which leads to slower cognitive processing and less speed of thought
289
.
In reality, PhA produces an improvement in health, both general and specifically cardiovascular health, at all ages, including old age. As the WHO and several state health agencies have asserted
290
, physical inactivity is the fourth RF of disease globally, and its reversal protects against several chronic diseases
291
. And it is clear that PhA leads to an
285
The Valenzuela et al, 2011, study showed neurotrophic compensations in the frontal lobe in people with high cognitive activity throughout life. FN # 280.
286
See table 7 (16.1), the studies confirm the importance of education as a PF of dementia. In the Scottish cohorts intelligence is assessed. In the second cohort (1936) the intelligence of the participant was statistically higher than in the first cohort (1921). (See FN # 52). This finding could be considered an exponent of the Flynn effect, that is to say, the increase in intelligence in psychometric tests in successive cohorts, due to two premises: the construction of these tests and the increase in the complexity of life that new generations must assimilate
( Flynn, 2013 ).
287
There are many informative monographs about obesity. One from Spain ( Campillo, 2010 ; pp: 225-229) tell us that the urban children frequently had a very sedentary life (school, TV, digital games); they do not have time for physical activity. If we add the industrial cakes and chocolates, that are delicious, then obesity begins in a vicious circle: fat children have problems with sports… more video games that are easier than sports…more snacks to relieve the tension of video games…
288
Mattson, 2014, 2015, described the anthropology of PhA, and included data from experimental animals that demonstrated more cognitive speed if the PhA is permitted ab libitum, showing better spatial orientation and having an increase of synaptic activity in the hippocampus.
289
Reed Hoang et al, 2015 that analysed the cognitive consequences of an excess of TV, and Basterra-Gortari et al, 2014, on the high mortality risk in persistent TV addicts.
290
WHO, 2002, considered that unhealthy diet and insufficient PhA were the leading causes of NCD (CVD, diabetes, obesity, cancer…). In 2010, WHO realized its recommendations about PhA and health ( WHO, 2010 ).
The Canadian Agency for Drugs and Technology in Health, 2014 published several analyses about PhA in diverse illnesses . In addition, the British NICE had a preliminary study ( Pavey et al, 2011 ) about this subject, but due to the scarce clinical trials of long duration did not give final conclusions, analogous to the Cochrane
Collaboration (Angevaren et al, 2008). Reiner et al, 2013, performed a review of the limited surveys of long duration (> 5 years) about the benefits of PhA in health; they underline the positive effect against NCD and AD.
Finally, the Spanish National survey about diet and PhA ( ENIDE, 2011 ) stressed that 46% of Spaniards are not engaged in any sport or PhA.
291
See Nocon et al, 2011 , with a systematic review ; Shortreed et al, 2013, with the Framingham data ; and the recent study of NHANES US ( Fishman et al, 2016) .
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improvement in cognitive performance, as has been demonstrated in various studies and a systematic review (it could also be beneficial in the prevention of sAD)
292
. Obviously, the effect of PhA has not been proved in all studies – it must be borne in mind that its measurement is problematic
293
and there are variations according to sex and age; but its effect is pronounced as the vast majority of studies not only report that it improves health, but even that it reduces mortality
294
.
In nearly all population-based cohorts, PA protects against cognitive decline in old age, MCI, dementia and sAD. There is a lengthy bibliography on its role as a protection factor (PF) for sAD, even in old age. This was also demonstrated in the Spanish NEDICES cohort, in which the elderly people had widely varied levels of physical exercise. Those who were classified as being physically active had less risk of dementia than those labelled physically inactive
295
.
The most incisive question at the moment is: “And why? Yes, why does physical activity improve general health, cardiovascular health, non-communicable diseases (NCD), and NDD, including sAD?”
Well, there are many explanations, but the specific bases of this action are unknown. Of course it is clear that a general level of PhA improves cardiovascular efficiency (it sets in motion the heart, respiration, blood circulation and the muscles) and it has positive effects on other cardiovascular diseases: HBP, obesity and diabetes. Furthermore, it improves oxidative stress in the cells (caused by free radicals ) and encourages the vascularisation of body tissues
296
. It also causes positive actions in the CNS (data from animals and humans) at the biochemical and cellular level: it decreases the cascade of cellular stress, reduces the markers of inflammation and resistance to insulin, and it increases angiogenesis and neurogenesis in the hippocampus (in animals)
297
. It has also been suggested that it might increase certain neuroprotective peptides and reduce stress hormones. “Oof! Too many things!” Yes, but it works and we must investigate further… And of course there are studies that show with neuroimaging that physical exercise improves the thickness of the cerebral cortex and the hippocampus (a structure related to memory, as we know)
298
And the million-dollar question: which PhA must we perform in order to earn all these gifts?
Well, we don’t know very well, but many investigations have been performed on the subject and there are some firm recommendations, as we shall see. But the truth is we don’t know with certainty the type of exercise, the duration or the intensity required. There is a fair amount of agreement that it must be aerobic exercise (which increases respiration and
292
Jedrychowski et al, 2007, analysed this subject in detail, and Sofi et al, 2010 performed a systematic review.
Radak et al, 2010, reviewed the possible effects on AD.
293
Koeneman et al, 2011, commented on the difficulty of PhA activity measurements: self-reported, questionnaires, and with objective measurements. Obviously, the last technique is ideal, but it is difficult to apply in population surveys of long duration.
294
Many studies have shown how PhA decreases mortality: Hayasaka et al, 2009 ; Samitz et al, 2011 (metaanalysis); Hupin et al, 201, Fishman et al, 2016, and Llamas-Velasco et al, 2016 in NEDICES .
295
Read Laurin et al, 2001; Lautenschlager et al, 2010; Larson et al, 2014 and Buchman et al, 2012 (that measured PhA with a device for objective measurements). The NEDICES cohort shows that High PhA decreases mortality: Llamas-Velasco et al, 2015, 2016. In addition, there are surveys in which a decrease of sAD incidence is clear: Rovio et al, 2005 ; Podewils et al, 2005, and also of VaD incidence ( Ravaglia et al, 2008 ).
296
297
See Carro et al, 2001 ; Brown BM et al, 2013 and Mattson, 2015 .
298
Brown BM et al, 2013, and Llamas-Velasco et al, 2015.
Consult Erickson KI et al, 2010, 2013
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oxygenation, such as walking quickly or running). The intensity? Some studies say the more the better, but the issue in a society of urbanites is that it’s not easy to get exercise without resorting to shorts and trainers, so some necessary minimums are required. The WHO and several state agencies have given recommendations ( table 17 -23d.1) for the various ages and types of person
299
.
Table 15 (23d.1). Recommendation of Physical activity (PhA), according to age*
Children and young persons (5-17) years
1) Children and young people aged 5–17 years old should accumulate at least 60 min of M-V intensity physical activity daily.
2) Physical activity (PhA) of amounts greater than 60 min daily will provide additional health benefits.
3) Most of daily PhA should be aerobic. V intensity activities should be incorporated, including those that strengthen muscle and bone, at least 3 times per week.
Adults (18-64) years
1)Adults aged should do at least 150 min of M-V aerobic PhA throughout the week, or do at least 75 min of V aerobic PhA throughout the week, or an equivalent combination of M and
V intensity activity.
2) Aerobic activity should be performed in bouts of at least 10 min duration.
3) For additional health benefits, adults should increase their M-V aerobic PhA to 300 min per week, or engage in 150 min of V intensity aerobic PhA per week, or an equivalent combination of M and V intensity activity.
4) Muscle-strengthening activities should be done involving major muscle groups on 2 o
65 years and over
1)Adults aged 65 years and above should do at least 150 min of M-V aerobic PhA throughout the week, or do at least 75 min of V intensity aerobic PhA throughout the week, or an equivalent combination of M and V activity.
2) Aerobic activity should be performed in bouts of at least 10 minutes duration.
3) For additional health benefits, adults aged 65 years and above should increase their moderate intensity aerobic PhA to 300 min per week, or engage in 150 min of V intensity aerobic PhA per week, or an equivalent combination of M and V intensity
4) Adults of this age group with poor mobility should perform physical activity to enhance balance and prevent falls on 3 or more days per week.
5) Muscle-strengthening activities should be done involving major muscle groups, on 2 or more days a week.
6) When adults of this age group cannot do the recommended amounts of PhA due to health conditions, they should be as physically active as their abilities and conditions allow a
Abbreviations. Min: minutes; M: moderate; PhA: Physical activity; V: vigorous
* PhA can be done in recreational time (walk, running, bicycling, plays and so on) o during the professional work.
Summarized from WHO, 2010; US Department, 2008 (specify the PhA for several types of people, e.g., pregnant women).
299
The US Department of Health… , 2008, and WHO, 2010 have published PhA recommendations for various ages and types of people, including pregnant women. These recommendations are similar in both documents.
The problem is not the advice, but its practice. In this respect, the primary physician’s advice on PhA is rarely followed (van Sluijs et al, 2004).
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The PhA for children and teenagers is demanding (see table 17 23d.1), but its efficacy has been shown
300
. For adults it was first said that the ideal amount was 30 minutes of moderateintense exercise five times a week; in some studies this was reduced to only three days a week
(the most recommended). But this exercise must be walking fast or running - a gentle stroll won’t do, because primitive man, from whom we inherited our physiology, didn’t walk around looking at the pretty little wild flowers in the forest or in the windows of non-existent shops. There are several interesting proposals, above all about minimums. A Japanese study suggests that only a little over 10 minutes’ moderate exercise every day is the recommended minimum and has generated a fair amount of controversy
301
. And several studies have quantified the number of steps to take (the use of pedometers is becoming routine, on watches and other systems) – for elderly people 3,000 steps a day (1,000 steps in 10 minutes is walking fast) is feasible
302
. What is certain is that this is a subject that worries scholars.
The American Health Agency will produce an update of its recommendations by 2018. In summary, doing physical exercise improves general health and prevents CVD and sAD. And it is good for those who have entered cognitive decline or dementia, as it decreases the pace of cognitive decline
303
. If we followed the advice that “some PhA a day keeps the doctor away”, it would change the world…
304
23E. Is there any better diet than the Mediterranean diet?
The Ancient Greeks believed that the basis of heath was: studying, physical activity and diet.
2,000 years later, this statement remains valid. But such general affirmations are rather easy to make and very difficult to test. What kind of studying, how much physical activity and what diet must we have in order to have good health? Therein lies the problem, dear Greek friends, so happy with their slaves… The advances in many aspects of diet have required meticulous research such as, for example, the discovery of the importance of fibre in the diet, which required a fascinating study: the comparison of diets in Great Britain and Africa (Uganda) managed to show that many of the digestive diseases in British people were caused by lack of fibre in the diet
305
. And the importance of intestinal flora or microbiota, our understanding of which is still very recent, is almost unbelievable. It turns out that we have trillions of minuscule eaters (microbiota) in our guts which help us to digest food, and whose activity is advantageous as they digest some foods that are useful to us. It is important that they work properly for our health, including neurological health; they could even lead to therapies for dementia
306
. These examples show the complexity of human diet in the light of 21 st
century
300
See Janssen & Le Blanc, 2010 .
301
The proposition of Miyachi et al, 2015 , feasible and with adequate bases, carries a reduction of dementia and
NDD risk (3.2%). It is worth remembering that 15 min of fast walking are equivalent to 5 min of running; and 25 min of running to 105 min fast walking for CVD prevention ( Wen et al, 2014 ).
302
303
Revew the interesting paper of Tudor-Locke et al, 2011.
304
See Verdelho et al, 2012 , and the systematic review of Groot el al, 2016.
305
Gallacher et al, 2005, with its interesting comments .
Hugh Trowell, an English clinician and investigator of digestive disorders (diverticulosis, constipation, etc) went to Sub-Saharan-Africa and compared the diets in England and this area of Africa and concluded that the high frequency of these disorders in the UK was due to the lack of food fibre in the English diet. A fascinating and not well-known investigation ( Trowell & Burkitt, 1986 ).
306
This subject is also incredible. We receive the intestinal flora from our mother. This little intestinal laboratory modifies food absorption. It has immunological and epigenetic functions, some of them related to neurological disorders ( Moos et al, 2016 ). Intestinal flora modification with drugs and probiotics could be therapies for dementia ( Alkasir et al, 2017 ).
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knowledge. Proving that a diet protects against a disease is a Herculean task (those Greeks again)
307
.
Demonstrations of the virtues of a diet are very difficult; large population-based studies (5-
10,000 participants) must be carried out, over a long time (five or more years) and in different populations. They need expert supervision because not everyone can follow a diet easily, and the diet interacts with environmental factors, and even the genome
308
. In the 20 th
century, most studies were about calories ingested, kind of food (vegetables, meat, fruit…) or the composition of what we eat (micronutrients – calcium, vitamins – or macronutrients – fats, proteins etc.), but now patterns or types of diet are becoming more and more significant
(healthy, Western, Mediterranean (MeDi), pro-inflammatory, vegetarian, Japanese, and others)
309
.
In this context of patterns or types of diet, came the brilliant and powerful PREDIMED
310 study (acronym from Pre vención con Di eta Med iterranea ), performed in Spain by Spanish researchers, which has shown the importance of this diet in the prevention of noncommunicable diseases (NCD) and cardiovascular diseases (CVD), and has brought attention to the research into their prevention. PREDIMED is a trial that has lasted 10 years (in all its phases) and has had the participation of three groups of people (all with vascular risk factors
(CVRF) who were followed for an average of five years. The 7,447 Spaniards were divided into three groups: one followed the MeDi, supplemented with olive oil, another supplemented with nuts and the third group had a normal low-fat diet (the control group). Those who followed the MeDi suffered 30% fewer cardiovascular events (infarctions, stroke or cardiovascular death), the primary objective of the study, and fewer NCD (diabetes, HBP and others) including MCI. The study has rounded off a series of investigations that indicated that the MeDi was one of the best for safeguarding health, and preventing the NCD which include
307
Launer, 2015, comment on the difficulty of dementia and AD prevention studies; diet clinical trials with selected foods or food supplements are almost impossible to perform (with the exception of short duration trials or with restricted populations). For that reason, the majority of these trials are not conclusive ( Temple, 2016 ).
This is why many authors maintain that diet cohorts are more valid ( Kemm, 2004 ).
308
The ideal diet and health investigations need thousands of participants, long duration and specialists for adequate performance and supervision (dieticians). Food biomarkers are expensive. Studies in animal diets cannot deliver the consequences for humans ( Freudenheim, 1999 ). Also, the genes-diet interaction is another complex story ( Ordovas et al, 2007 ), diet even affects telomeres ! ( García-Calzón et al, 2015 ) and intestinal microbiota and the intestinal-microbiota risk of dementia ( Alkasir et al, 2017 ).
309
Read Hu FB, 2002 , to analyse the types of diets; and Luchsinger & Mayeux, 2004 ; and Hu N et al, 2012 as reviews of several diets and AD risk. It is not possible to mention all healthy diets; we will refer only to the
MeDi, possibly the leader of healthy diets. Its beginning as a diet with scientific data is due to a US biologist,
Ancel Keys, Mr Cholesterol, who after his observation of cholesterol and cardiac infarction in Madrid and
Napoli stressed the importance of the MeDi and set up the Seven Countries Study ( Carmena, 2006 ). This study demonstrated the low mortality associated with MeDi and led to the MONICA survey that showed the low incidence of cardiac infarction associated to MeDi ( Gerber & Hoffman, 2015 ). Ancel Keys, who practised the
MeDi throughout his life, died at 101 in his hometown, Minnesota.
310
The PREDIMED study is a complex trial, whose leaders were MA Martínez González and Ramón Estruch, and has generated many publications of high impact. Decreasing CVD incidence by 30% with the MeDi is a success ( Estruch et al, 2013; Martínez-González et al, 2015 ). It is necessary to emphasize that the PREDIMED study has shown the utility of MeDi in CVD and also in NCD such as obesity ( Bullo et al, 2011 ), HBP (Storniolo et al, 2015 ), DM2 ( Salas-Salvadó et al, 2016 ), depression ( Sánchez-Villegas et al, 2013 ), cancer, mainly breast cancer ( Verberne et al, 2012 ). There are also publications showing effects on MCI ( Martínez-Lapiscina et al,
2013; Valls-Pedret et al, 2015 ), but there is no research in dementia or AD.
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sporadic Alzheimer’s (sAD)
311
. PREDIMED was preceded by investigations based on diet patterns
312
such as DASH (diet against HBP), the new diet, and MIND (Mediterranean-
DASH intervention for Neurodegenerative Delay).
After reading all this you could ask: “Can what we eat really protect us from diseases?” Well, yes, of course. We’ve already recalled the Greeks, and in modern times, in which diet is part of a (developed) world where the food industry is important and everything to do with food is scrutinised by administrations and consumers, we must answer this question in the affirmative. In many diseases there is such tangible evidence as in the CVD.
“And has this been proved for sAD?” A study of diet and the appearance of sAD is very complex – CVD have acute and obvious onset: stroke and myocardial infarction, or have biomarkers like diabetes (blood-sugar), whereas the onset of sAD is insidious and requires diagnosis by experts. However, there are studies that have investigated this, with positive results (the MeDi protects against Alzheimer’s)
313
. Nevertheless, it would be necessary to wait for adequate trials than firmly establish MeDi (and other diets) for preventing AD. As the
MeDi is what is followed in the Mediterranean countries (including Spain) we have only briefly mentioned other healthy diets: like the “prudent” diet, DASH and MIND. Also, there are other diets that are considered healthy around the world (standard Japanese and Indian diets, and others).
The following question arises: what really is the MeDi – what does it consist of? Well, it’s the diet followed traditionally in Mediterranean countries: a diet rich in fruit, vegetables of all kinds, pulses (2-3 times a week), nuts, and olive oil as the main source of fat, dairy products
(with cheese and yoghurt), a lot of fish and little meat… and wine? Well, yes, wine with
311
After the Seven Countries study (FN # 326), many authors, mainly French, Italian and Greeks published on this subject. But it was Antonia Trichopoulou, a professor of Clinical Epidemiology in Athens U (around a thousand publications in MEDLINE) who demonstrated that the MeDi, decreased cancer incidence and mortality
(EPIC study realized in several countries with more than 70,000 participants) ( Trichopoulou et al, 1993, 2005 ).
Other studies underlining the MeDi benefits in general health are shown in Sofi et al, 2008 ; van de Rest et al,
2015 . There are also nutrigenomic studies in MeDi ( Lairon et al, 2009 ).
312
DASH diet (Dietary Approach to Stop Hypertension), is a type of diet quite similar to MeDi, but without olive oil. It has efficacy for treating HBP and CVD ( Appel et al, 2006 ). There are several diets that have been use to prevent CVD and cognitive decline ( Wengreen et al, 2013 ) . In general, diets with plenty of fruit and vegetables seem to have good results ( Liu et al, 2000 in the Women’s Health Study) . MIND ( Mediterranean-
DASH Intervention for Neurodegenerative Delay ) aims to decrease cognitive impairment and AD incidence
( Tangney et al, 2014; Morris et al, 2015 ); this diet includes 10 types of healthy foods (green vegetables, pulses, olive oil, fruits, chicken and others) and five unhealthy (red meats, butter, margarine and cheese, pastries and sweets, and fried potatoes and fast foods). There are more healthy diets. The “Prudent” diet includes great quantities of fruit, legumes, whole grain cereals, fish and low fat milk and a minimal quantity of meat, sweet beverages and fast food. The typical western diet is full of calories, with red and processed meat and fast and take away food; it is considered an unhealthy diet ( Fardet & Boirie, 2014 ).
There so many types of diets that is not possible to offer a summary. Only examples: Nagumo, 2016 recommends only one meal a day and the rest of the day: tea, beverages and nuts as snacks. He sold more than
100,000 copies of his book. There are also some authorities that recommend periods of food abstinence (several hours a day 1-2 days a week, or periods of relative fasting) to imitate the dietary flexibility of ancient huntergatherer habits ( Mattson, 2015; Freese et al, 2018 ).
313
Nikolaos Scarmeas, a Greek investigator from Columbia U. in New York, is one of the leaders of MeDi research. He demonstrated in several surveys that MeDi prevents AD and mortality ( Scarmeas et al, 2006, 2009 a, b ), and MCI ( Scarmeas et al, 2009 b ). Several reviews maintain that the MeDi prevents several neurological illnesses ( Psaltopoulou et al, 2013; Féart et al, 2009; Yusufov et al, 2016) and delay the MCI conversion to AD
( Cooper et al, 2015 ). The problem is that there are not yet adequate trials to corroborate clearly the diet surveys data, and several authors do not credit the diet cohort findings or the majority of RCT with diets (bias, short term follow-up) and demand better studies and RCT (See Kane et al, 2017; Lechner et al, 2017 and FN # 16).
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meals (family or group meals). But a picture paints a thousand words: figure 30 (23e.1) shows a MeDi pyramid (there are many of them and not all are the same) with the desirable frequency of foodstuffs
314
.
Figure 30 (23e.1).
Mediterranean diet pyramid
All foods are healthy in the amount reviewed, being the tip of the pyramid with which there is more care not to exceed.
Abbreviations: r: rations; >: more; <: less. The potatoes rations does not includes frites…
Modified from Bach-Faig et al, 2011 (see text and FN # 328-331).
And another question arises: Are people still following the MeDi in Mediterranean countries?
Well, this is the crux of the matter – this diet is being lost in these countries. The studies that analyse this subject are unequivocal: the MeDi is hardly followed now, above all by children aged 2-10, Spain included
315
. So what is to blame? Mothers? Schools? The whims of children? Advertising? Coca Cola or fast food? A little of everything, but if we want to prevent Alzheimer’s and other NCD, it seems reasonable to accept the advice of the Greeks on diet and return to the traditional Mediterranean food, following the recommendations of
UNESCO, which has declared the MeDi Intangible Cultural Heritage.
314
USDA (U.S. Department of Agriculture) produced nutrition pyramids 20 years ago, and every five years they are updated. They have been successful due to their visibility. The USDA, 1993, pyramid was printed in English and Spanish ( Lu M, 2006 ). But its construction is difficult because it is necessary to summarise scientific data and theres is pressure from several lobbies: food industry, consumer associations and so on. Next updated in
2018. Many institutions, such as Harvard U, produce pyramids (www.thenutrition.org). There are several about
MeDi, the one presented in the figure 30 summarises a consensus of Mediterranean countries ( Bach-Faig et al,
2011 ).
315
See León-Muñoz et al, 2012 . It is curious, but the MeDi ( da Silva et al, 2009 ) is spreading in northern
European countries and decreasing in Mediterranean countries like Spain (Spanish children mainly do not follow it) in the European context ( Pereira-da-Silva et al, 2015 ) as the Spanish official survey certifies ( ENIDE,
20011 ).
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An important subject within diet in modern urban life, where we have convenience and processed food is the role of public and health administrations in the regulation of the food products present in supermarkets, and those foodstuffs which in general must be reduced: salt, saturated (and trans) fats and sugar. Why? Quite simply because our ancestors did not eat these foodstuffs in the quantities that we do now, and our metabolism isn’t prepared for them
316
.
“And what about these superfoods that are so fashionable these days?” It’s true that there are foods that contain the necessary nutrients and are in fashion (cranberries, quinoa, chia seeds, salmon, olive oil and others), which have received this pompous name and a lot of attention in the media – through smart marketing. But although they are healthy, probably the best
“superfood” is a varied and constant Mediterranean diet
317
.
23F. More risk and protection factors – or only associations?
Over 100 individual modifiable risk factors (RF) and protection factors (PF) have been described for Alzheimer’s disease (sAD)
318
. But their importance is lesser or more dubious
(less proof) than those mentioned – it is even possible that many are only associated without being causal. Let’s see. Having white or little hair is associated with age – the older you are, the more likely you are to have white (or little) hair, and although dementia and sAD are associated with ageing, we mustn’t deduce that little (or silver) hair is a cause of dementia, it’s only an association (or if you like, a marker of senescence ). Table 18 (23f.1) shows a wide range of putative RF and PF, some of which will possibly be associations without causality, and others have not achieved sufficient consistency to be qualified as RF or PF. We are not going to review them all: the most plausible have already been mentioned; those that have generated rivers of ink or have contradictory data will be discussed briefly.
The first is an unpreventable risk: gender. Do women have more risk of suffering from dementia than men? The data are contradictory – from a population-based perspective there are many studies that show greater prevalence in women (there are more elderly women than men because they live longer), but the risk, i.e. the incidence of sAD is similar when the education is also similar. And in the pathological studies, this difference does not exist. Thus it appears sensible to conclude that there are no differences in AD-type pathology. If in some population-based studies the risk is higher in women, it might be because Alzheimer’s
316
Hyseni et al, 2017 reviewed this transcendent subject, and the efficacy of administrative measures for food control. Taxes for sweet beverages and for excessive fat are coactive measures in order to attempt to get the food industry to decrease sugar and trans- and saturated fats in their products. Food labels have less efficacy because many people do not read them. It has been proved that a decrease in TV advertisements determined reductions in the calorie intake of children. Spain does not have a good position compared to other European countries in food regulations ( Lloyd-Williams et al, 2014 ) .
317
Superfoods are more a marketing matter than a scientific subject. It is clear that superfoods and food supplements are healthy but they cannot replace natural foods (and global diet). EFSA ( European Authority for
Food Regulation ), 2012, do not define superfood. See the commentary on olive oil as a “superfood” in the next section .
318
Consult, Xu et al, 2015 a . More recently, an umbrella review ( Bellou et al, 2016 ). It is necessary to bear in mind that many statistically relevant associations between a variable and the presence of dementia or sAD could be only an association and not an RF (this could be the case in depression or benzodiazepine intake and AD).
Remember the concept of RF (chap # 10). The CPG on dementia of the Spanish Ministry of Health, 2011 , of whose committee this author was a member, has a wide review on this subject.
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manifests itself more easily in women (above all if they have studied less)
319
. But many authors do not see it like that.
Table 16 (23f.1). Dementia and AD possible risk ( and protection ) factors #
(Exhaustive table)
Genetics
Several genes and alleles* (RF)
APOE 2 (PF)
Family sphere (RF)
Familiar accumulation of cases (genetic)
Low education level (mother) and work (both parents), low SES, many offspring (>7), maternal or familial excessive stress?
Demographics (RF)
Chronological age, female sex?
Foetal (toxic exposures, hyponutrition, hypernutrition?)
Foetal-birth (RF)
Prematurity, low weight and cranial circumference, stunting
Infantile development (RF)
Low SES, poverty, scarce cognitive and emotional attention along the two first years, stress
Illiteracy or low education (CogR)
General Health (RF)
Infantile bad health (multiple infections, chronic inflammations, and others)
CVRF: obesity, dyslipemia, HBP**, metabolic syndrome in adulthood, DM-2, carotid and systemic atherosclerosis, heart disease, auricular fibrillation, stroke, and others
Chronic illness: bronchitis, kidney insufficiency, severe cranial trauma, hearing loss, general anaesthesia?, dental loss?, hypothyroidisms?, virus C repeated infections,? C. pneumoniae infections? and others
Depression, sleep disorders, neuroticism, lack of vital perspective?
Comorbidity and frailty in the elderly
Biological determinations
Anaemia?, hyperhomocystinemia?, folate deficit, deficit of vitamins B o D?, and others? (RF)
Drug intake
Benzodiazepines use? (RF)
NSAID, estrogens? (PF)
319
Jorm, in his monograph, 1990, summarised all the studies performed in the world. He concludes that the dementia risk for men and women is similar. If there is a minimal difference, it will be only due to the greater risk in very old women ( Jorm & Jolley, 1998 ). In the EURODEM survey, the risk was higher for women, but at the beginning of the 20 th
century, the educational level of women was clearly inferior to that of men. This fact was different in the large USA and Canada surveys in which basic education were similar in both sexes (see
Bermejo-Pareja et al, 2013, 2016 b ). The pathological data described ( Miller FD et al, 1984 and Sandberg et al,
2001 ) showed that the typical AD cerebral lesions were analogous in the brains of men and women.
138

Nutrition
Healthy diets (MeDi, Prudent diet and others), coffee intake (PF)
Antioxidants?, vitamins E, C, and B?, n-3 acids?, fish intake? (PF)
Excessive intake of saturated and trans fats? (FR)
Life style (FR)
Sedentarism (reduced PhA)
Toxic habits (alcohol***, tobacco, illicit drugs)
Low intellectual activity (CogR)
Chronic stress?
Social isolation (scarce social contacts)?, reduced size of the home?
Toxics (FR)
Metals (copper, lead, and others), aluminium in water, and others?
Work exposures ( welders, electromagnetic fields )?, children and youth rural life?
Air pollution, pesticides, and others
# More cited with some relevant publication and elaborated with data of many authors. (PF were the inverse of RF are in general)
?: Doubtful FR or FP
* See Chap # 11; **HBP is a RF for dementia in adulthood, the inverse in the very old
***Alcohol intake: <4 drink/day could be PF of dementia
Abbreviation: See Abbreviation list
In the area of modifiable RF and PF there are three PF of certain importance because every one of us has them nearly every day: coffee, omega-3 fatty acids and olive oil. Other RF are very frequent: depression, co-morbidity (many associated diseases) in elderly people, toxic environmental factors (pesticides, air pollution and others), which have more and more studies, above all in the foetus and small children, and which are a public health issue
320
.
Coffee has been the subject of two systematic reviews as a PF for dementia and sAD, with positive results: the two studies agree that there are enough data to confirm its role as a PF.
Good news for coffee drinkers. “And how much coffee?” Not more than two cups in one go, and not more than five a day. Tea and other herbs (some medicinal) haven’t had so much luck, as their studies have been inconclusive
321
. Omega-3 fatty acids, above all from marine sources (such as in sardines), have been proposed as a PF in several studies and reviews, but the trials have not reproduced the observational studies (table 22.1 and 23.1) – its role in the
320
United Nations, 2011, and Beaglehole et al, 2016, have proposed to decrease NCD by 25% by 2025 and their mortality. WHO, 2012, endorsed making dementia prevention a priority. Nevertheless, dementia prevention depends greatly on the precise measures taken in public health in the realm of dementias and AD, mainly in two important areas: environmental toxicity control ( Barouki et al, 2012; Killin et al, 2016 ) and nutrition ( Hyseni et al, 2017 ).
321
Coffee and dementia has two systematic reviews ( Liu et al, 2016 and Wu et al, 2016) that confirm its role in decreasing sAD incidence. Healthy coffee intake has clear recommendations (no more than five cups a day and others) ( Nehlig, 2016 ). It was found that quercitin and not caffeine is the neuroprotection agent in coffee ( Lee et al, 2016 ). There are reviews of other herbal products in dementia (tea in Panza et al, 20015; medicinal herbs in
Hügel, 2015 ); none were clearly positive.
139

prevention of sAD is not definite
322
. Olive oil is one of the most important compounds of the
Mediterranean diet (MeDi) as a source of fat. Also, there are studies that show the importance of its components (oleocanthal and phenols) which in various experimental studies have shown biological activity in transgenic and in vitro mice as neuroprotectors for AD, which reinforces the epidemiological studies performed with the MeDi in cognitive decline and sAD, and provides the bases for future studies
323
.
Among the risk factors, perhaps the most important and undervalued in this review is depression. Why? Well, because depression is a common companion of dementia and sAD, and it is difficult to accept that old depression can be an RF of dementia or AD, since any brain lesion, personal or “social” problem can cause it. Nonetheless, several systematic reviews have endorsed this RF which is considered treatable (certain antidepressants improve the signs of ageing in experimental animals), but depression is normally treated. Despite this, many authors consider it a dubious RF, like the intake of benzodiazepines or sleep disorders, which can be a clinical manifestation of dementia or sAD. Besides, depression is usually accompanied by little physical and social activity and even life activity, and separating depression from its own associations is not at all easy
324
.
It seems clear from a clinical perspective that co-morbidity (CVD (myocardial infarction), cerebral (stroke, cranial trauma), systemic (kidney diseases or chronic bronchitis) and multiple co-morbidity (bad health, frailty)) is an RF of cognitive decline, dementia and possibly sAD, but such a mixed RF is difficult to analyse, and as with the previous RF, it would require a thorough analysis, which is beyond the scope of this monograph
325
. The same is true of exposure to environmental and work-based toxins, and even general anaesthesia in elderly people. All the same, the subject of neurotoxicity is becoming more and more important due to its frequency in big cities, whose increase seems inevitable. This century has seen an increase in knowledge of the neurotoxicity of many compounds. It is known that more than 200 chemical compounds are neurotoxic for adults, although it is in the foetus and small children where they can more easily have their effects, as the developing
322
Sala-Vila et al, 2016 showed that the ingestion of omega-3 of marine origin decreases mortality; Beydoun et al, 2014 maintain the protective role of this product in dementia, but AD prevention is under debate ( Hu N et al,
2013, and Burckhardt et al, 2016).
323
Italian authors have been the leaders of the basic biological neuroprotection investigations on olive oil.
Rigacci, 2015, comments on the activity of its phenols, and Abuznait et al, 2013,
WKHFHUHEUDO$ ȕ HOLPLQDWLRQE\ oleocantal; in addition, olive oil modulates tau protein fibrillation ( Monti et al, 2012 ). In transgenic mice, the olive oil phenol, oleopurine, has demonstrated anti$ ȕ DFWLYLW\ Luccarini et al, 2015 ). These basic studies give biological support to the N. Scarmeas and A. Trichopoulou MeDi investigations (FN # 328). Certainly, in both types of research the olive oil was a part of the MeDi. It would be very interesting to perform diet studies with olive oil quantifications; there is biologic support for these types of investigations.
324
Several surveys ( Kessing & Andersen, 2014 ) and systematic reviews (Ownby et al, 2006; Da Silva et al,
2013; Bellou et al, 2016 ) show the association between adult depression and dementia or AD incidence in old age. However, there are criticisms of these findings from Bazin & Bratu, 2014, and the Rotterdam survey, Mirza et al, 2016, since depression, like mild loss of memory, could be the early manifestation of AD. Meanwhile, an expert panel considered depression as a treatable RF for dementia ( Deckers et al, 2014, Bellou et al, 2016 ). In the NEDICES cohort, previous depression was not an RF for dementia ( Olazarán et al, 2013 ). New investigations would be necessary for a definite conclusion.
325
Many studies have analysed comorbidity as an RF for dementia. The NEDICES showed that suffering stroke and general subjective bad health (marker of comorbidity) were clear RF for dementia ( Bermejo-Pareja et al,
2008; Llamas-Velasco et al, 2015 ). Other works from: Reitz et al, 2011 ; Beydoun et al, 2014 ; Deckers et al,
2014; Anstey et al, 2015 ; Wu YT et al, 2015 found analogous results . Song et al, 2011, dedicated a specific review to this subject . General health has biological plausibility for being a dementia RF.
140

brain can be damaged by small quantities of toxins. In fact, the hypothesis of impact during this period is one of those held by the followers of the development origin in the genesis of diseases (complex, systemic and neurological -Parkinson’s, sAD) as well as others of early brain development (schizophrenia, autism)
326
. Air pollution in the big cities has been shown to be an RF for stroke and it is probable for sAD
327
.
Another RF for AD is severe cranial trauma (which damages the blood-brain barrier). It is not very important in percentage terms, but it has been shown that wearing a helmet on a motorbike can reduce immediate mortality, the consequences and sAD
328
.
Table 18 (23f.1) and figure 31 (23f.1) summarise what has been described and make it easier to understand the importance of each factor in the genesis of dementia and sAD.
Figure 31 (23f.1).
Main RF and PF of dementia and AD
(According its likelihood)
Modified scheme of Baumgart et al, 2015. The grey arrows (with decreasing tone) show the likelihood of the risk and protective factors in dementia/AD; black grey: high certainty; grey: moderate certainty; light grey: low certainty.
Abbreviations. SCT: severe cranial trauma; HBP: High blood pressure; PhA: Physical activity; Diet:
Healthy diet, MeDi and others; Social activity; Cognitive activity; Alcohol, Coffee in moderate quantity.
326
Grandjean & Landrigan, 2006, described how in more than 80,000 registered chemical products, only 200 in humans and 1,000 in animals (but not yet in humans) had demonstrated toxicity. Killin et al, 2016 performed a systematic review of the environmental RF (pollution, pesticides, aluminium and so on), analysing the evidence for their possible causal toxicity in NDD, and Tanner et al, 2004, 2014 , did analogous research in US veterans.
327
Air pollution microparticles, harmful ozone and several gases: CO, nitrogen (and sulphur) monoxide and dioxide are probably RF for sAD ( Calderón-Garcidueñas et al, 2015 ) in children and adults. However, not only for AD, but also for other neurological illnesses as a large USA study has indicated ( Kioumourtzoglou et al,
2016) .
This possibility is biologically endorsed by the early AD and PD effects on the nasal neuroepithelium and olfactory centres. This monograph did not comment on the causal AD hypothesis of aluminium and other metals because they are very complex subjects, with no clear causation and without therapeutic treatments, despite the
Canadian scientist, McLachlan ( McLachlan et al, 1991 and Wang et al, 2016 ).
328
Satz, 1993, and Guo et al, 2000, detected cranial trauma as an RF for sAD, that increases its risk with its severity; Barnes et al, 2014, and Ling et al, 2015 reviewed its biological bases and Baumgart et al, 2015 its population data. General anaesthesia could be an AD RF in old age but there is only one adequate study in Asia
( Chen et al, 2014 ).
141

Alzheimer’s disease (AD) is a cause for worry. This worry is personal for those who have passed the age of 75 (from this age it starts to become frequent), familial, due to the effort involved in looking after a family member with AD, and a matter of social and medical despair because of the absence of a cure and its irremediable ending.
At the end of this monograph, it is worth explaining that the concept of Alzheimer’s has experienced many shifts since its appearance
329
. A little history. For Kraepelin, who invented the eponym for his protégé Alois Alzheimer, pre-senile and senile dementia were caused by a deficit in brain blood flow. The neurofibrillary threads (NFD) that his protégé described on the neurons of a 51-year-old patient allowed him to separate the two dementias by an objective feature, and give his protégé a disease and a professorship. But, science has many twists and turns.
The science of the 20 th
century, based on hospital studies, updated the concept in 1978, uniting the old pre-senile and senile (without a clear cause) dementias into a single concept:
Alzheimer’s-type dementia, and changed its origin from vascular to “neurodegenerative”. The reason for these changes was that neither the clinical nor pathological manifestations allowed either this separation or vascular causality. Alzheimer’s became defined by a clinical feature: progressive memory loss and two histological findings: NFD and senile plaques (SP), as well as more subtle findings: synaptic and neuronal loss. From the 90s, genetics gave the concept another twist; in this decade it was shown that there are two kinds of Alzheimer’s: pre-senile familial Alzheimer’s (fAD), which is very rare (less than 1%) and caused by a single defective gene, and sporadic or “primary” Alzheimer’s (sAD) (99%), which is normally senile and where genetics is as important as in other diseases such as HBP or diabetes. And one geneticist came up with an explanatory theory. The genetic errors detected were related to the metabolism of the amyloid precursor protein , whose fragment beta-amyloid (
$ ȕ LVGHSRVLWHG in the SP; the genetic errors in this protein would generate hyper-production and the
DFFXPXODWLRQ RI $ ȕ LQ WKHP DQG LWV WR[LFLW\ ZRXOG FDXVH WKH UHVW RI WKH SDWKRORJLFDO alterations and dementia ( amyloid cascade hypothesis). This theory was applied to fAD and
OLNHZLVHWRWKHV$'FDVHVLQWKHODWWHUWKHDFFXPXODWLRQRI$ ȕ ZRXOGEHHQFRXUDJHG by ageing. In that decade, the deficit in cerebral cholinergic transmission was also confirmed, which when improved with drugs, stimulated the cognition of patients with AD. Despite this being a great milestone in the therapy of Alzheimer’s, they have not managed to halt its progression. Both discoveries have generated a galaxy of studies in the neurosciences, supported by genetics, cellular biochemistry, the pharmaceutical industry and health administrations, all looking for a pill (the so-called golden or silver bullet) that could cure or delay this scourge of the elderly
330
. And, it hasn’t been found. This monograph weighs up the scientific bases of the amyloid cascade hypothesis, which was almost unanimous until a decade ago, and describes other opinions, some doubtful and others contrary (yet another twist… that will perhaps “unscrew” the concept).
329
The concept of AD has changed in the 21 st
century with an almost Copernican shift, in French it could be called: “bouleversement” (modification with disorder); there are positions that are very critical of the 20 th century AD concept (e.g., Whitehouse & George, 2008; Richards & Brayne, 2010 ; Lock, 2013; Khachaturian &
Khachaturian, 2015 ).
330
“Magic elixir” is other denomination of this incredible therapy ( Khachaturian, 2016 ).
142

“And are the new hypotheses more likely?” Well, no they aren’t. And that’s where we are, without a unanimous etiopathogenic hypothesis, and without a precise biological marker that allows a clinical or pathological diagnosis: the current ones, in both cases are only probabilistic. Also, the traditional pathological foundation has been questioned by populationbased studies with brain necropsy, which have shown that in the brain of patients diagnosed with sAD in the population, there is a heterogeneous mix of lesions: AD-type (SP, NFD), myriad vascular lesions, and others: atrophy of the hippocampus, disruption of the subcortical white matter and various neurodegenerative disruptions. For this reason, the name dementia-Alzheimer’s syndrome is being introduced, distancing us from the unity agreed in
1978
348
. And the 20 th
century concept of Alzheimer’s has continued to be undermined: the disorder does not start in senescence , but rather decades earlier – one or two decades with subtle clinical data, 3-5 with pathological studies, and starting from childhood if we give validity to pretangles (initial NFD), or to the biological trends that look for the origin of complex diseases in infancy (even in foetal life), or to the biology of systems , which analyses all the molecular machinery of the cell: the origin of Alzheimer’s (its risk or seed) would occur in early infancy (2-3 years when the brain is formed and “programmed”) and a little later when more than 95% of the brain is formed (6-7 years), and it would be developed in youth and throughout life, manifesting itself in old age. This monograph explains all of this without taking sides. And if the conceptual difficulties weren’t enough (they aren’t), no drug
(despite the intense race of studies and trials) can yet delay or cure the disease: including anti-
$ ȕ YDFFLQHVDQGH[FHSWLRQDOO\UHILQHGDQWL
-
$ ȕ GUXJVXVLQJKXPDQLVHGDQWLERGLHVZKLFKDLP to cure or delay. It still hasn’t been achieved.
“So what is Alzheimer’s disease?” Well, we don’t rightly know – this is clear. The hypotheses that explain this disease have be enunciated but not analysed. That would be too much for a scientific dissemination monograph. Its intention is modest – it aims to be practical, albeit with theoretical support, but practical. Scientific proof has been sought in order to convince the non-believers (and there are many) that preventing dementia and Alzheimer’s is possible
(there are results that confirm it). In the developed countries the incidence of dementia is decreasing and its prevalence is stabilising. Yes, it is a fact like the one observed in other diseases before a causal or pharmacological therapy (cholera, tuberculosis, myocardial infarction), whose incidence and mortality decreased with improvements in health conditions
(hygienic and environmental), and the increase in education in the population. This has not been the case in the Third World.
The main preventive strategies are: care during pregnancy and after birth, attention and education in infancy, a physically and intellectually active life, with the prevention of vascular risk factors (which isn’t easy) and a healthy diet. But, no, not in old age or during adulthood, but rather from infancy when the brain is forming. And then we must always maintain a healthy lifestyle.
“A whole monograph full of scientific citations for a conclusion so simple that the Romans and Greeks guessed it ( mens sana in corpore sano)
331
and eat well to be healthy?” Let’s not
331
The name dementia-Alzheimer’s syndrome conveys the possible existence of several “Alzheimer diseases” from a pathological and biological point of view (FN # 112). This situation has been contributed to by the cerebral neuroimaging alterations that are better detected ( Zhao et al, 2016 b ) and the cerebral lesions associated
143

be defeatist – the message of the monograph is not a truism. The message appears simple but it is not. Alzheimer’s is very complex and has multiple risk and protection factors, and its prevention, which we are currently trying to demonstrate with randomised population-based trials, is even more so. But it is worth making a final summary, which as with all summaries will be a simplification. This text contains three clear premises. First, we still cannot cure
Alzheimer’s. Second, its prevention or the delay of its appearance is possible: this is being achieved in developed countries. And third, prevention must be performed from the earliest possible age. And finally, it is stated that although prevention is possible, it is not easy. The risk factors must be controlled – most of the population (or society) don’t control them. For prevention to be effective we must take care (over generations) of the health and education of the mother before, during and after pregnancy
332
so that she can conceive, feed and look after the baby during the time that the infant brain and the health (physical and mental) of the child is forming. The baby must be protected from an adverse environment, avoiding infections and noxas (from alcohol, tobacco or drugs to air pollution, because its brain is very “tender”). It must be given a suitable emotional environment (this is not easy without a pleasant familial and social context), and cognitive stimulation, with attention and toys that encourage the development of its intelligence (the cognitive reserve is important). The child needs strenuous physical activity, which is being lost with urbanisation and an excess of TV and video games.
The knowledge of more than one language from childhood is desirable
333
. Education that tends to increase intelligence must be present throughout life (work and lifestyle), and this must include social participation and continued physical exercise, whose minimums are fairly clear nowadays after many studies, as are the measures to prevent vascular risk factors with drugs and other methods. It is also known which diet or diets are suitable throughout life, although there is still much to be learned here. All of these measures require the participation of society and its public and private administrations in many aspects: from the elimination of environmental toxins to campaigns about the care of pregnant women and children, including food
334
control and the social integration of people with dementia. Let’s be honest, most people don’t put into practice the recommendations that originated in Ancient Greece, but are not widely followed in the 21 st
century. In the developed countries there is, according to current data
335
, an unstoppable epidemic of obesity and diabetes, half of those with high blood pressure don’t follow their treatment properly, and many women smoke, drink alcohol or eat too little or too much during pregnancy and don’t breastfeed their babies… Moreover, who does the physical exercise necessary to keep fit? Not many people: more than half of
Spaniards don’t do it, and less than 10% follow the traditional Mediterranean diet
336
. Not even our children do the amount of exercise recommended by the WHO, or follow the
Mediterranean diet. Investment in public health is needed in order to more rigorously control to AD that are better understood such as: cortical atrophy ( Savva et al, 2009 ) or neurodegenerative changes
( Josephs et al, 2015 ).
332
“ Healthy mind in healthy body ”, a quote that did not have the same meaning as it does nowadays to define health, since it was obtained from a satirical text of Juvenal (2 nd
century).
333
The European Union carries out a programme of information on pregnancy and maternal care which is highly remarkable, and in all the languages of the Union, with charming slogans such as “ do not eat for two, think for two ”; see: www.project-early nutrition.eu/.
334
Society and its government professionals are necessary and irreplaceable, especially in environmental protection ( Killin et al, 2016 ) and in food control ( Hyseni et al, 2017 ).
335
336
NCD Risk…, 2016 a, b, alert us to this explosion of obesity and diabetes.
Pereira-da-Silva et al, 2015, in European preschool children, and ENIDE, 2011 (official dietetic Spanish survey) showed us that the majority of Spaniards (70%), nowadays, scarcely follow the Mediterranean diet.
144

environmental aspects, including food. The Third World has to improve: maternal and infant nutrition, equitable education, the list goes on… although people with dementia integrate well into rural environments…
This monograph has described with data (based on proof) a wide range of information (on theoretical and practical aspects) about what has to be done to prevent Alzheimer’s, and in the end, firmly recommends that protection from this disease must begin in infancy and continue throughout life.
145

146

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Reducing risks, promoting healthy life . Geneva, World Health Organization. 2002: https://books.google.es/books?hl=es&lr=&id=epuQi1PtY_cC&oi=fnd&pg=PR9&dq=WHO+
(World+Health+Organization).+Dept.+of+Noncommunicable+Disease+Prevention+and+Hea lth+Promotion.+Active+ageing:+a+policy+framework.+Geneva:+World+Health+Organizatio n.+%E2%80%8E2002&ots=N3G2bZykMn&sig=W_YSGZe851wghR_nWNLTfUveNwE#v
=onepage&q&f=false
WHO ( World Health Organization). Adherence to long-term therapies. Evidence for action .
2003: http://apps.who.int/iris/bitstream/10665/42682/1/9241545992.pdf
WHO (World Health Organization ). Global recommendations on physical activity for health .
Geneva. 2010; http://www.who.int/dietphysicalactivity/factsheet_recommendations/en/index.html
WHO ( World Health Organization) .
Mental Health: Dementia: a public health priority.
2012: http://www.who.int/mental_health/publications/dementia_report_2012/en/
WHO ( World Health Organization). Meeting report: nurturing human capital along the life course: investing in early child development. World Health Organization, Geneva,
Switzerland, 10-11 January 2013
WHO ( World Health Organization). Draft WHO global action plan on the public health response to dementia 2017-2025 . WHO Discussion Paper (version dated 5
September 2016): http://www.who.int/mental_health/neurology/dementia/zero_draft_dementia_action_plan_5_0
9_16.pdf
www.genetests.org.
GeneTests: an online genetic information resource for health care providers. And, GeneReviews: https://www.ncbi.nlm.nih.gov/books/NBK1116/
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*
AD : Alzheimer’s disease is an NDD that divided into, sAD , sporadic or essential AD, polygenetically and environmentally caused; and fAD, familial or monogenetically caused
AD (chap # 4 and 11).
AD without dementia: new term for AD in which the person has no symptoms of dementia but exhibits positive biomarkers in CSF or neuroimaging (MRI or PET) characteristic of AD; is analogous to pre-symptomatic AD ( Dubois, 2010 in ref).
AD, early (or initial or very mild AD ): Minimal memory loss or cognitive decline with clinical and biochemical characteristics of AD ( Johnson KA, 2016 in ref ). All these terms are controversial
AD , established: clinically clear AD
ADNI: Alzheimer’s Disease Neuroimaging Initiative , is a study mainly promoted by the NIH to investigate the early diagnosis of AD and its evolutions according to its clinical and biomarker (CSF, neuroimaging) characteristics ( Weiner, 2013 in ref ). Similar ADNI studies are taking place in Europe, Australia and Japan.
Ageing: It is easily define by chronological age. From a biological point of view ageing could be defined by the functional impairment that time determines in the physiological cellular and organism processes.
Ageing, successful (or healthy): Ageing without illnesses (or not serious or chronic illnesses), and without disability and pathological cognitive decline.
Allele : Any alternative form of a gene that can occupy a chromosome locus and express certain characteristics. In humans, there are two alleles, one on each chromosome of a homologous pair. One allele comes from the father and the other from the mother and can be identical or different (e.g., allele ApoE could be ApoE3/4 or ApoE4/4). See ApoE4 and Chap
# 11.
Alexia : Inability to read despite intact visual abilities caused by cerebral lesions.
Alostatic : (alostatic burden): Corporal capacity to be adapted to environmental stress by means of physiological changes.
Amyloid beta (
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-42 aminoacids is accumulated in senile plaques in AD. Some authors write beta-amyloid.
Amyloid cascade hypothesis : Physiopathologic hypothesis that maintains that AD is mainly caus
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Aminoacid : Elemental part of proteins (each protein is formed by a chain of multiple aminoacids, in general more than 50 aminoacids).
Amnesia : loss of memory (remembering). There are several types of amnesia or memory loss, see memory.
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Infantile amnesia: Loss of memories of the 3-4 first years that children (and adults) experience because of cerebral maturation.
Anabolism: Part of the cellular metabolism that constructs its biological components
(enzymes, proteins, etc).
Anomia : Difficulty in remembering names or words. This occurs in normal people occasionally. It is only abnormal if it is very persistent.
Aphasia: Difficulty in language production (motor aphasia) or in its comprehension
(sensorial aphasia). They indicate a lesion of the cerebral language circuit (third frontal circumvolution and medial temporal lobule connexion in right-handed people).
Agraphia : Acquired disorder of writing due to cerebral disorders (AD or others).
ApoE: Abbreviation of Apolipoproteine E (specific type of protein that metabolizes lipids).
ApoE4 : Allele 4 of the gene that produces Apolipoproteine E. It is a risk factor for AD. Allele
2 is a protective factor for AD. Humans have several allelic forms of this gene: ApoE2/2,
ApoE2/3, ApoE 3/3, ApoE 2/4, ApoE 3/4 and ApoE4/4. This last form has the highest risk for
AD. See Chap #11.
Apoptosis: Death of cellules without the inflammation characteristic of NDD. The rest of the cellular destruction is sucked in by the cell and is not destroyed by several mechanisms such as occurs in cellular necrosis
Apraxia: Acquired disorders of skilled movement after cerebral damage (such as in AD) that are not caused by sensory or motor incapacity.
Axon : Prolongation of the neuronal soma that permit fast neuronal conduction of stimuli.
BADL (Basic Activities of Daily Living). Such as feeding, personal grooming, bladder and bowel control, dressing, ambulation and so on. BADL are conserved until the last dementia evolution period. Several indexes and scales evaluate this BADL in the clinical setting very easily (e.g., Katz index).
Beta-amyloid ( ȕ
A) , see amyloid beta .
Biology of systems ( or system biology or system theory): This is a part of molecular biology. System biology studies, in an integrated and profound way, the interaction of the molecules in the inner part of the cellule. System biology analyses genetic information
(transcriptomic), protein data (proteomics), lipids information (lipidomics) and so on.
Biomarker: Biological trait that is associated with a clinical variable or illness. If it is not of a biological nature, it is called simply marker .
Caloric restriction: Diet of decreased caloric intake without causing malnutrition This procedure increases survival in animals, including primates, but this is not so clear in humans in which some adverse effects are caused.
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Case-control, study : Method of analytic epidemiology that compares the possible RF of a disease between the cases (which suffer from this disease) and controls (persons without the disease), usually adjusted for (with analogous) age and sex. A study of this type permitted the establishment of the cause of toxic syndrome in Spain (toxic oil ingestion).
Catabolism : Some part of cellular metabolism that destroys the biological components
(proteins, lipids and so on) in several cellular structures.
Cell reprogramming : Experimental methodology allowing the transformation of differentiated cells into induced pluripotent stem cells (iPSCs). This methodology could be interesting for the design of future therapies in ageing and age-related disorders.
Cerebral Reserve (CeR) : It indicates the nervous tissue size and quantity of a person. People with high nervous matter quantity are protected against lesions that could cause cognitive decline and dementia (It could be a static biological reserve as opposed to the dynamic CogR of cognitive reserve.
Clinical Practice Guidelines (CPG): Systematically developed statement to assist the clinician and patients’ decisions in specific health situations (in general, performed according to EBM rules).
Clinical trial (randomized): Clinical study performed to demonstrate the clinical efficacy of a drug or other therapeutic procedure. The trial must be randomized and compare the therapeutic measures with a placebo. Usually it is double blind (neither the doctor not the patient knows who is treated with the therapy or the placebo). International institutions (FDA in USA, EMEA in Europe), State institutions and ethical Committees regulate the trial methods.
Clinical trial with parallel groups: When the trial comprises two groups, one group of patients take the drug and another group take the placebo, with the numbers, age and sex being similar in each group. This type of trial is usual in AD therapeutic investigation.
Cochrane Collaboration: International team studying memory of the brilliant epidemiologist , Archie Cochrane (1890-1988). It performs systematic reviews by international experts.
Cognitive capacities (or domains). It has many definitions. It is clear that cognition is composed of multiple domains such as attention, memory, language, perception, visuospatial abilities, and executive performance, which are formed of processes that are more elementary.
Cognitive enrichment : Manipulations in experimental animals (mice) that are performed to increase their cognitive performance (mazes, running wheels and other games, the Disneyland for these little animals). See Milgram, 2006 in ref .
Cognitive reserve (CogR): Theoretical construct considering that there exists a mental capacity (composed of multiple cognition capacities: memory, language, knowledge acquired throughout life). All of these could be integrated in a functional biological reserve (multiples synaptic connexions forming many neuronal networks) that prevent the cerebral lesions that cause dementia from having clinical manifestations.
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Cognitive stimulation : T hemed activities to orientate and actively stimulate cognition through various sessions for cognitive decline patients, mainly in groups and in Day Centres.
Cognitive training : Teaching strategies (e.g. mental imagery) to improve verbal learning and other cognitive functions that could be implemented in individual or group sessions mainly in
MCI, demented or AD patients.
Cohort : Group of people who are followed or tracked over a period. In general, these people have a common characteristic (census list, age or others). It is used in prospective studies of long duration (cohort studies). This term is reminiscent of Roman cohorts (groups of soldiers).
Chronic disease: Sickness that persists for a long time (more than 12 months); many of them are complex diseases.
Complex disease: Illness in which multiple genes (polygenetic) and environmental factors intervene. These diseases are usually chronic. Examples: diabetes, obesity, HBP; many authors includes AD.
Cost-effectiveness analysis : Measures the net cost of providing a service as well as the outcome obtained.
Cortical areas : The cerebral cortex is divided in lobules (frontal, temporal, parietal and occipital) and within the lobules there are several areas defined histologically or by their function (sensorial, motor, association or others).
Cortical association areas: Zones of the cortical lobules that have the function of associating among several other analogous areas. These areas are phylogenetically recent and the basis of many high-order cognitive functions and tend to be affected by AD.
Day Centre: Centres that take care elderly people during the day (sometimes they are located in a hospital or nursing home). In general, these centres are for persons with cognitive decline or AD.
Dementia : Syndrome of cognitive decay (mainly) persons unable to perform IADL and social integration. It has many causes, with AD and VaD being the most frequent.
Dementia-AD syndrome: Term recently applied to sAD due its pathological heterogeneity, mainly in the old-old.
Dendrites : Neuronal prolongations, in general branching in shape (although there are many forms) that mainly receive input impulses from axons or others neurons.
Diagnostic criteria, probabilistic : These are not based on firm, well-established, criteria
(gold standard) but on a diagnostic probability. Nevertheless, all clinical diagnostic medical diagnoses must be considered as probabilistic because have only a high probability of being right (85-95%). Only genetic diagnosis could be 99.9% correct.
Diagnostic gold standard: Basic diagnostic criteria for an illness. It could be a biological determination (hyperglycemia in diabetics), or a clinical judgement (DSM-IV criteria for dementia, as examples).
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DNA : Abbreviation of deoxyribonucleic acid. It is the primary genetic material of all cells. It is the template to form RNA. With its variants of four aminoacids (thymine, glycine, cytosine and guanine) it writes the genetic code.
DOHaD : Abbreviation of the Developmental Origins of Health and Disease association.
This association investigates the origins of health and illness from the very early beginnings of life (foetal and infancy). See website: www.dohadsoc.org
DSM: Abbreviation of the Diagnostic and statistical manual of mental disorders . Series of manuals of psychiatric diagnosis performed by the powerful and very international American
Psychiatric Association (USA). The DSM-V (2013) manual changed the well-known predementia states (MCI) to minor neurocognitive disorder and dementia to major neurocognitive disorder.
Dysphasia : Difficulty in producing or receiving language. When it is intense, it is called aphasia (sensorial or motor). See aphasia.
Ecological survey : A study in which the units of analysis are populations (or groups of people) rather than individuals. Example: the AD prevalence in several regions of England was related to the aluminium content in drinking water (hypothesis of aluminium toxicity in
AD, not confirmed).
Elite survival . Group of persons with extraordinary health (that allows them to avoid dementia, AD or other serious illnesses) and reaching the age of 90-110.
Epidemiology : Study of frequency and distribution of illnesses in human populations
( descriptive epidemiology ). This discipline also studies and analyses the causes and RF of these illnesses ( analytic epidemiology ).
Epigenetics : Studies soft heredity , that is to say, the non-Mendelian type of heredity transmission.
Epistasis : Interaction between genes (not only additive) that contribute to a phenotype.
Evidence based medicine (EBM) : From the 90s there has been opinion in medicine (widely accepted) that advocates that the medical practice should be guided by scientific data such as clinical trials and systematic reviews. The practice of EBM means integrating individual clinical expertise with the best available clinical evidence.
Executive functions (or performance): Higher cognitive functions that underlie planning, organization, and goal-directed behavior. It could be extended to the integration of cognitive and emotional processing. In clinical practice, a simple evaluation of the patient’s executive capacity is fingering on a table with a rhythm: e.g., 1-3, 3-1, 1-3 and so on.
Exposure : Contact of any type (biological or environmental) that a person experiences and that could be a risk or protective factor for an illness.
Foetal early programing: The term that indicates the metabolic pathways that are developed in the foetus when experiencing environmental stress. Currently, the concept of DOHaD
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( Developmental origin of health and disease) is preferred ( see : www.dohadsoc.org and FN #
201)
Free radicals : Biochemical compounds that are produced in cells during ageing and that are toxic to the cells (see oxidative stress).
Life expectancy: The average number of years an individual at given age is expected to live if current mortality continues to apply. Could be at birth or at a given age.
Gamete : Sexual chromosome.
Gene : A segment of a molecule of DNA that contains all the required information to perform the synthesis of a protein or other biological product (molecules). It is the biological unit of heredity (hard non-modifiable heredity).
Genome : Complete genetic information of a being or a person.
Genotype: Genetic burden of a person integrated into the DNA (cellular nuclei).
Glia (neuroglia) : The supporting cellules of the NS. There are several varieties: astrocytes, oligodendrocytes and microcytes. The glia cellules are more numerous than neurons and have several functions apart from structural support: nutrition, neurotransmission and others.
GWAS : Abbreviation of genome-wide association studies. This is a new and powerful genetic study technique.
Heredity, soft : Heredity based on epigenetic mechanisms in contrast to the hard heredity based on the genetic information contained in the DNA molecules
Hippocampus : Complex anatomic structure (resembling a seahorse) included in the medial temporal lobule. Its definition changes according to authors and may include the hippocampus itself, subiculum and entorhinal cortex. This structure is necessary for different types of memory, mainly explicit memory (Chap # 6).
IADL (Instrumental Activities of Daily Living) .
Activities that require good cognitive functioning such as money control, shopping, preparing meals, controlling domestic equipment (TV, radio) and so on. Begins to fail in the early period of dementia. Many scales evaluate this function (e.g., Pfeffer scale).
Incidence (of an illness): Quotient between the new cases of an illness (numerator) in a population (denominator), and in a determined period (in general one year). Usually is given in new cases per 1,000 people in a year.
Induced pluripotent stem cells (iPSC) . Human iPSCs constitute an unlimited source of patient-specific cell types that could be used for regenerative medicine, drug screening, and disease modeling (including AD). See Soria-Vallés in ref.
IQ: Abbreviation of intelligence quotient, measured by the WAIS test. It is the quotient between the cognitive performance score of a person and the score of the control group adjusted by age and sex. In general, the mean is 100 and the standard deviation 15.
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Intelligence : Abstract concept with many definitions. In medicine, psychometric intelligence is used (measured with cognitive tests such as WAIS ( Wechler Adult Intelligence Scale ). But, there exist other “intelligences” (emotional, musical, etc) correlated with a common factor known as general intelligence or factor G.
Intelligence, artificial (AI) : Imitation of human intelligence by computers.
Intelligence, crystalized : Type of intelligence that involves the knowledge of language, social relationships, general world view and its rules (familial, politics); it is like our encyclopaedic dictionary. This concept came from the WAIS.
Intelligence, fluid: Practical or operative intelligence. The WAIS in one of the sub-tests that defines it.
Limbic (system) . Subcortical structures comprising the cingulate gyrus, fornix, septum, amygdala, hippocampus and others. It is related to emotion, drives, and motivations, but its definition varies in different neuroscientific books.
MCI : Abbreviation of mild cognitive impairment. Theoretical entity to define a precise predementia syndrome with a definition with international consensus ( see Winblad, 2004 in ref). Its main characteristic is objective memory loss and frequently, but not always, it is the initial phase of dementia or AD.
MEDLINE : Main database of biomedical literature (more than 29 million abstracts of biomedical publications) and other related information. Created by the USA Federal
Government (NIH) and established in Bethesda, Washington. Its access is free by means of the engine www.pubmed.com
. There are other important biomedical databases such as
EMBASE.
Memory : Ability to retain information and experiences. It represents the fundamental adaptive capacity of the brain.
Memory, autobiographic : Memory of one’s own life.
Memory, episodic : Conscious memory of long-term remembering for storing episodes or events that are personally experienced. It is characterised by four Ws: “who, what, when and where” aspects of an event. In very old events it is called remote memory.
Memory, explicit (or declarative) : Explicit or declarative memory is a conscious memory.
Declarative knowledge is available as conscious recollection, and it can be brought to mind as remembered verbal or nonverbal material (image, sensation, words and so on).
Memory, immediate (short term) or primary: It is the memory that registers a digit list or a series of numbers for some seconds (In general, 4-7 digits; e.g., a phone number); it depends mainly on the prefrontal lobe and associated circuits of attention. Nowadays the term working memory is used more because it has better experimental confirmation.
Memory, implicit . These memories are unconscious such as skill abilities. What is learned is embedded in acquired procedures and is expressed through performance. There are several
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types: procedural (like cycling, car driving), priming (unconscious memory facilitation in several tests).
Memory, procedural. It is an implicit memory. Refers to sensory motor or skilled based learning (riding a bike, playing piano) that is not necessarily accessible to conscious experience.
Memory, secondary (or long-term): Memories that persist more than several seconds-1 minute. Could be conscious (episodic) or unconscious and require hippocampus integrity for its adequate functioning.
Memory, semantic : Long-term memory; its content is general knowledge about objects, general events (historical, political), concepts and the meaning of words. It is abstract memory that is not personally or temporally related.
Memory, subjective : Also called metamemory. It is the impression that each person has of his own memory. Frequently much stressed subjects refer to loss of memory that is not confirmed in psychometric tests.
Memory, working : Encompasses the representational processes that allow us to keep information active or in mind for a short time period. It is a combination of attention, concentration and immediate memory. It permits us to manipulate some data in the consciousness in order to obtain an objective. For some authors it is analogous to short-term memory.
Meta-analysis : A systematic review that uses quantitative methods to summarize its results.
Metabolism : Refers to the physiological processes of the cellular components that permit normal cellular functions.
Mitochondrion (mitochondria, plural) : Organelles (small spherical or rod-shaped) found in the cytoplasm of cells. They are the principal sites of energy generation in the cells.
Mitochondria have their own DNA and RNA heredity, almost exclusively from the mother.
Mendelian, heredity: Type of heredity whose transmission follows Mendel’s laws. If the abnormal genetic allele is dominant, 50% of the offspring will manifest the illness. If the allele is recessive it will be masked by a dominant allele when the two occurred together in a heterozygote.
Myelinisation : Process of covering the neuron axons with myelin (lipid structure from oligodendrocytes). Myelinisation allows quick nervous impulse transmission.
Nervous system (NS) : Composed of the central nervous system (CNS), brain and spinal cord, and peripheral nervous system, that is to say, peripheral nerves.
NPT : Abbreviation of non-pharmacological trial . Clinical investigation to probe the efficacy of non-drug therapy, but rather other therapeutic treatments such as psychological therapies or others.
Neural network : Neuronal arrangements that subserve various neurobehavioral domains.
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Neural plasticity : Neurons possess and retain the capacity for alteration and growth. Capacity of neurons and their synapses to establish new circuits that permit them to overcome possible cerebral lesions.
Neurites, dystrophic : Neural processes that contains paired helicoidally filaments (PHF) or other membranous substances surrounding SP. See Fig 10.
NCD: Abbreviation of non-communicable disease, this term alludes to chronic noninfectious, non-contagious chronic diseases such as obesity, diabetes, CVD, cancer, AD and so on, in which the Western life style is a RF in its genesis
Neurocognitive disorder, mild (or minor): DSM-V diagnostic category similar to MCI.
Neurocognitive disorder, major: DSM-V diagnostic category analogous to dementia.
Neurodegeneration (Neurodegenerative disorders -NDD) : Term that referrers to a process of neuronal death with apoptosis and is applied to a group of neurological diseases that are slowly progressive such as Parkinson’s or Alzheimer’s disease (NDD). See Calne, 1994 and
Dickson, 2011 in ref .
Neurogenesis : Formation of new neurons. In humans, it is very high in the foetus and first years of life and scarce in the adult brain (exceptions are the hippocampus, olfactory bulb and striatum).
Neurofibril: One of the slender fibres inside the cell body of neurons and extended into all of these processes. It is formed in part by neurofilament (thread-like structures of about 100
Armstrong in diameter).
Neuroleptics : Drugs with antipsychotic and sedative effects that are frequently administrated to demented persons with hallucinations or psychotic symptoms.
Neuropil : Felt work of the terminal processes of axons and dendrites interspersed among the neuron and glia in the grey matter of the CNS.
Neuron : Nervous cellule, the main integrant of the NS. There is a great quantity of neurons in the NS (10
10
-10
12
). Neurons encode and transmit the NS information.
Neurotransmitters : Chemical substances released at the neuronal axonal termination that modulate or enable the synapses (examples, acetylcholine, GABA, dopamine, etc).
Neurotransmission : Transmission of nervous information, neuron to neuron, and neuron to glia (or from neurons to muscle) by means of synapsis (see synapsis).
Neurotubules : Tubular structures visible in the cytoplasm of neurons by electron microscope.
These neurotubules permit the circulation of substances along the neurons.
Oxidative stress: Several biologic processes generate oxygen reactive compounds (free radicals) that can damage the cellular proteins or the DNA. These compounds could increase the ageing and increase the likelihood of AD.
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Paired helical filaments (PHF) . Twisted abnormal paired filaments that form the NFT (see
Fig 11 -6.8).
Phenotype: External appearance of a being (or person).
Phenotype and genotype thrifty hypothesis: This hypothesis indicates that the thrifty genes confer a survival advantage in times of nutritional deprivation. In the same way the thrifty phenotype hypothesis maintains that thriftiness prepares the foetus for an environment with nutritional deprivation.
Plausibility, biological : Comprehensible explanation from a biological underpinning of a cause, effect or RF that could be associated to an illness or a physiological finding of any kind.
Polypeptide : Part of a protein composed of many aminoacids.
Prefrontal, lobule, areas : Anterior part of the frontal lobule that has increased greatly in phylogenetic evolution (it is greater in humans than in non-human primates). The prefrontal area is related to behavioural control.
Prevalence (disease) : It is defined as the quotient between the number of people that suffer from an illness and the total population in which these ill people are found. If in one village of a thousand inhabitants are 90 dementia cases, the dementia prevalence would be 90/1,000, that is to say, 9%.
Prevention (illness) : Acts to eliminate, mitigate or to delay an illness.
Pretangles : Abnormal tau accumulation that precedes tangles. See Braak, 2011 in ref.
Prion diseases : The illnesses that are caused by prions (infectious proteins) such as mad cow disease, Creutzfeldt-Jakob disease and others. They could be infectious (transmitted) or genetic.
Prion-like transmission: The transmission in NDD of abnormal folded proteins (such as tau and
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Proteasome : Cellular (including neurons) organelle specialized in protein synthesis
Protective factor (PF): The inverse of a risk factor. Its presence protect against an illness or health risk.
Prosopagnosia : Difficulty in recognizing human faces
PPA: Abbreviation of a protein of great molecular weight that has the amyloid beta polypeptide within its chains
Pseudodementia : Syndrome that simulates dementia. Usually it is caused by psychiatric illnesses that simulate dementia such as depression (depressive pseudodementia) or schizophrenia.
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REST: Abbreviation of 1-silencing transcription/neuron-restrictive silencer factor. It has recently been discovered that REST is induced in the ageing human brain and regulates genes that mediate cell death, stress resistance and AD pathology. Its modulation could be a future therapy for AD and ageing. See Lu T in ref .
Risk, attributable : The rate (proportion) of a disease in exposed individuals that can be attributed to the exposure
Risk , attributable (in population). With a given outcome, exposure factor, and population, the attributable fraction among the population is the proportion by which the incidence rate of the outcome in the entire population would be reduced it the exposure were eliminated. But there are several meanings. See Greeland in ref .
Risk factor (RF) : This term has several meanings. In general, it is considered as a lifestyle behavior or and environmental exposure (tobacco) or other (genetic predisposition) that is known to be associated with an increase of risk of an illness (AD) that it is necessary to prevent. If it is not causal it is called risk marker.
Risk, relative (RR) : The ratio of the risk (or death) of those exposed to the risk to the risk among the unexposed (synonymous with risk ratio ).
“Odds ratio” (OR). (Synonymous with cross-product ratio, relative odds): Indicates a quotient of two odds. (Probability of occurrence of an event and non-occurrence). It has several meanings. See Last, 2001 in ref .
RNA : Abbreviation of the ribonucleic acid that transmits the genetic information from the cellule nuclei to the cellular soma. It has several types messenger, microRNA and others.
Screening : Presumptive identification of an unrecognised illness by the application of tests, clinical examination of other procedures (e.g., blood exam) that can be applied rapidly and in general in a wide population (e.g. Mammography to detect breast cancer).
Senescence: Ageing in popular terms. In biology it indicates the physiological decay in mammals after reproductive maturation (could be inverse in some animals).
Senile plaque (SP) : Characteristic lesion of AD. These are complex lesions, formed by
$ ȕ deposition (in the center), located in the neuropil and with others cellules around it; when the
SP is surrounded by dystrophic neurites, is called neuritic plaque . See chap # 6. Fig 10 (6.7).
Sensitivity : Proportion of people with the target disorder who have a positive test.
Specificity : Proportion of people without the target disorder who have a negative test.
Study, analytic . It is usually concerned with identifying or measuring the risk factor or health effects of specific exposures (such as tobacco exposure and its health consequences). In contrast with a descriptive study, that does not analyze RF. The three analytic studies are cross-sectional, cohort and case-control.
Study or survey, clinical : Study realized in clinical settings. In patients that attend clinical consultations (hospital or others).
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Study, retrospective. This type of research is undertaken to obtain information from a patient database of a disease to clarify its characteristics, or to test etiological hypotheses about a disease like in case-control studies.
Survey, prospective : Study that obtains information prior to the beginning of the illness (or the object of the survey). These are also called longitudinal or cohort studies.
Survey, population-based: Study performed on the general population such as political polls.
These studies are achieved in populations to eliminate the bias due to clinic-based studies.
Syndrome, metabolic of the adult: Syndrome characterized by: obesity, HBP, dyslipidemia,
(low HDL), insulin resistance and others, which is a RF for CVD.
Syndrome, malignant neuroleptic . Syndrome caused by an adverse reaction to neuroleptics that could be severe or even lethal.
Synapsis : Connection between neurons that could be executed in different ways (electric, by neurotransmitters). In the synaptic connections and in their networks NS information such as memory or knowledge is encoded, although there are another ways to encode NS information.
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-synuclein): Protein whose deposition is characteristic of several NDD such as Parkinson’s disease (integrated in the Lewy bodies) or others.
Systematic review : A summary of the medical literature that uses explicit methods to perform the literature search. In addition, it achieves a critical appraisal of the individual studies with objective categorization of their quality.
Tangle (Neurofibrillary tangle-NFT) : Characteristic lesion of AD. Intracellular knot or clumps of neurofibrils seen in several parts of NS (see Chap #6,12and Fig11A).
Tau: Structural neuron protein that partly forms the neurotubules. See Fig 11 B.
Taupathy : This refers to any alteration of the tau protein (that stabilize the neurotubules). Tau protein disorders are observed in AD and other NDD (mainly degenerative Parkinsonism).
See Lee in ref.
Telomerase: Cellular enzyme with several functions. One of these functions is to regulate the telomere length. Telomerase is able to synthesize telomeres from an RNA template, providing a compensatory mechanism to continuous telomere shortening.
Telomere: A term applied to each of the extremities of a chromosome. The shortening of telomeres is associated with several chronic disorders and with ageing. See Fok, 2017 in ref .
TDP-43 (TAR DNA-Binding Protein 43): Abnormal folded protein associated with several
NDD (amyotrophic lateral sclerosis) and several dementias (AD included) and hippocampal sclerosis .
Test, cognitive: General reference to the multiple cognitive tests that assess the various cognitive domains (e.g., MMSE, Wechsler intelligence) and so on.
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Transgenic (mouse): Also known as knock-out mouse. These are animals with modified genes (in general, including genes of a human disorder). Example: the PSN1 of fAD transgenic mice is used to study AD physiology.
Transmission, intergenerational: Trait transmission over several generations that does not depend on hard heredity (DNA), but rather epigenetic mechanisms or the environment-gene interaction). See chap # 11.
Transition, epidemiologic : The change in the illness model from nutritional and infectious diseases to chronic diseases: obesity, diabetes, CVD, cancer and others associated with ageing.
Validation therapy : NPT that is applied to old-old or demented persons to reduce their stress and increase their dignity and happiness, by means of a holistic vision of their biography.
Variable : Any trait that could be analysed statistically (e.g., age, physical activity, diet and so on).
Verbal fluidity: Capacity to produce a list of words. It is an elementary psychometric test that measures the capacity to list as many fruits or some kind of animal as possible in one minute. Less than 12-14 words/minute could be abnormal.
White collar and blue collar workers. Plastic definition used in population-based survey to differentiate administrative workers (white collar) from manual workers (blue collar).
White subcortical substance : Subcortical area near to cerebral ventricles formed by nervous fibres (myelin covered) that are affected during ageing and dementia illnesses such as VaD and AD.
* This glossary includes, simplifies or modifies terms taken from several authors, mainly from
Dorland’s Dictionary, 2009; Last, 2001; Lockhard, 19977; Gómez-Polledo & Bermejo-
Pareja 2006; Rizzo & Eslinger , 2004 and Sackett, 2000 (see ref).
234

The list of acknowledgments is long and begins with the most experienced in scientific and educational works. Thus, I must thank the professors and academics: Federico Mayor
Zaragoza and José Manuel Ribera Casado for their prologue and presentation and their encouragement to carry out this work. I must also highlight Prof. Luis Collado, Head of the
Dpt of Medicine U Complutense (Madrid, UCM) for his push to create the Extraordinary
Chair of “Alzheimer's and neurodegenerative diseases”, and for his support of this monograph, as well as the promoters of the chair, Pfizer GEP SLU and Juan Guillén-Coosur
Foundation and its communication Director, Ana Sánchez. In addition, at the UCM, I want to thank the librarian of the Faculty of Medicine, Javier Jorge, and his team, mainly Amanda
Castillo, for obtaining many texts on this subject and Laura Lopez for arranging the economic-administrative aspects of the aforementioned chair.
I would like to express my gratitude to my colleagues at the UH12O, for having been readers of this work: the professor of Neurology: Jesús Hernández-Gallego, and the neurologists:
David Pérez, current Head the Dpt. Also, my thanks go to Alberto Villarejo and Sara Llamas, from the Dementia Unit; Julián Benito-León and Saturio Vega (family doctor and geriatrician) who are very active collaborators in the NEDICES cohort, the study on which I based many data of this monograph. I have to give a special mention to Teodoro del Ser and
Javier Olazarán for the meticulous reading of the manuscript and criticisms. Also, I give thanks to the members of the CIBERNED, the neuroscientists: Jesús Avila, Eva Carro and
Fernando Bartolomé, and the epidemiologist Agustín Gómez de la Cámara for their reading of the draft. The librarians of UH12O: JM Estrada, Gema Serrano and Mª J Muñoz have carried out, as always, the continuous job of obtaining many bibliographical citations, many more than those included in the text.
The professor of psychology, Israel Contador, has reviewed the chapters of greater cognitive content and Professor Emeritus of Medicine, Federico Hawkins, has evaluated topics related to diabetes and complex diseases. I must highlight as collaborators in the NEDICES study JM
Morales, Álvaro Sánchez Ferro and Fernando Sierra-Hidalgo; I would like to mention all the collaborators in this study that are cited in the portal: www.ciberned.es/NEDICES; although their contribution has been very valuable, the list is too long. I also want to thank the creative,
Jorge M Gibert for his patience with the ever-difficult medical drawings, and the expert in editorial work, Eduardo García Rojo. In the new designs of the English version another creative, Jesús Navarro, modified some figures and did other work with special care. In the
English version I have to thank the patience of the English professional translator, Joe Healey, for correctly giving the main text a colloquial air and for carefully reviewing my translations of the most technical aspects of the monograph. I am grateful for the brilliant work of the scientific journalist, Sonia Moreno, who has made this monograph more accessible.
I thank the editorial collaborators of VisionNet, mainly Rafael Castillo (with whom I share a lasting friendly relationship) and Jesus Navarro, for his multiple editorial efforts.
And, last but not least, I want to thank the instigator of this book: the professor, academic, companion at H12O, and famous surgeon, Enrique Moreno, because with his courageous message he convinced me to carry out this endeavor.
235

236

Figures
Figure 1. (2.1). Publications on AD prevention in Medline ...................................................... 3
Figure 2. (4.1). Age distribution of the two types of AD ......................................................... 11
Figure 3 (5-1). Alzheimer’s disease evolution (preclinical and clinical periods) .................... 14
Figure 4 (6.1). Scheme of a neuron .......................................................................................... 17
Figure 5 (6.2). Diagram of the CNS functioning ...................................................................... 19
Figure 6 (6.3). The ´triune´ brain (Cerebral structure according to evolution) ........................ 20
Figure 7 (6.4). Brain representation in lateral and sagittal vision ............................................ 22
Figure 8 (6.5). Main functional subdivisions of the cerebral cortex ........................................ 23
Figure 9 (6.6). Hippocampus representations over the cortex surface ..................................... 24
Figure 10 (6.7). Hippocampus representations over the cortex surface ................................... 25
Figure 11 (6.8)
6HQLOHSODTXHDQGQHXULWLFSODTXHZLWK$ ȕ EUDLQGHSRVLWLRQ
....................... 26
Figure 12 (6.9). Neurofibrillary threads in neurons (neurofibrillary tangles, NFT) ................. 26
Figure 13 (6.10)
$EQRUPDOSURWHLQ$ ȕ DQGWDXGHSRVLWLRQLQWKHEUDLQDQGLWVSDWKRORJLF evolution over time ................................................................................................................... 27
Figure 14 (7.1). Scheme to explain the cognitive reserve (CogR) ........................................... 31
Figure 15 (10.1). AD risk and protection factors (Causal pie) ................................................. 43
Figure 16 (11.1). Main epigenetic mechanisms ....................................................................... 47
Figure 17 (12.1). Classic photograph of Alois Alzheimer ....................................................... 51
Figure 18 (12.2). Original drawing of neurofibrillary threads (neurofibrillary tangles -NFT) by
Alois Alzheimer ........................................................................................................................ 51
Figure 19 (12.3). Emil Kraepelin.............................................................................................. 54
Figure 20 (14.1). Evolution over the time of the clock-drawing test in a patient suffering AD
.................................................................................................................................................. 62
Figure 21 (15.1). Stairs type of evolution in the cognitive decline .......................................... 64
Figure 22 (15.2). Prevalence of cognitive states in the baseline of NEDICES cohort ............. 66
Figure 23 (16.1). Dementia prevalence increase and countries (by socioeconomic development) ............................................................................................................................ 68
Figure 24 (19.1). Cholinergic brain neurotransmission ............................................................ 83
Figure 25 (19.2). Cascade amyloid hypothesis......................................................................... 85
Figure 26 (22d.1). Risk dementia/AD factors evolution over the lifetime ............................. 110
Figure 27 (22.e1). Cerebral pathology in dementias in relationship to age ............................ 115
Figure 28 (22.e2). Study areas of NEDICES cohort .............................................................. 116
Figure 29 (23a.1). Elderly life expectations in Spain and its projection for the future .......... 126
Figure 30 (23e.1). Mediterranean diet pyramid ...................................................................... 136
Figure 31 (23f.1). Main RF and PF of dementia and AD ....................................................... 141
237

Tables
Table 1 (2.1). Main risk factors (RF) and prevention factors (PF) for sAD. ............................. 5
Table 2 (6.1). Main cerebral lesions associated with Alzheimer’s disease .............................. 28
Table 3 (10.1). Criteria for establishment risk factors (RF) in illness ..................................... 42
Table 4 (13.1). Mains clinic memory types and its cerebral networks (localization) .............. 57
Table 5 (16.1). Main cohorts with decreasing elderly dementia/AD (over time) .................... 70
Table 6 (20.1). Non-pharmacological therapies (TFT) in dementia/Alzheimer ..................... 87
Table 7 (21.1). Clinical trials for sAD prevention ................................................................... 93
Table 8 (21.2). European trials of primary prevention of dementia and AD ........................... 94
Table 9 (22a.1). Risk and preventive factors for sAD in the family ....................................... 99
Table 10 (22c.1). Risk factor for dementia and sAD in infancy and youth ........................... 109
Table 11 (22d.1). Risk and protection factors for dementia and sAD during adulthood ....... 113
Table 12 (23.1). Modifiable RF and PF for Alzheimer disease ............................................ 121
Table 13 (23.2). Risk and protection factors for AD at population level. ............................. 121
Table 14 (23a.1). Factors that promote cognitive successful aging ....................................... 126
Table 15 (23d.1). Recommendation of Physical activity (PhA), according to age ................ 132
Table 16 (23f.1). Dementia and AD possible risk ( and protection ) factors .......................... 138
238

Thematic index
[ Relevant citations in text pages, figures (F), tables (T), foot notes (FN), bibliography (b) and glossary (g) ]
A4 trial, 92,FN#183,166b,169b,175b,204b
AAD-SPRA study, 116,FN#248
Aberdeen cohort, 1,29,108,FN#222,183b
Acetylcholinesterase inhibitors (ACI drugs)
ACI (drugs), 65,66,81,82,87,89,93,94
see tacrine, donepezil, rivastigmine, galantamine
ACTIVE study, 89
Activity
-mental/intellectual, 30,112,121,126,130,139,141,151b
-physical, see physical
-social, 74,119,140,141, see social and SES
ADAMS study, 97,FN#193
ADI ( Alzheimer’s Disease International ), 68 , FN#132 , 71,148b,217b
ADNI ( Alzheimer’s Disease Neuroimaging Initiative) , 72,171b,185b,213b,222g
Adoption, children, 106
ADRDA ( Alzheimer’s Disease Related Disorders Association), 166b,188b
-NINCDS -ADRDA criteria for dementia, FN#140
Adult ( adulthood) diseases, 1,2,T1,36,58,105,108,122,138,143,147b
-AD and, Chap22D
--lifestyle/risk, T9,110,158b,165b,178b
-neurogenesis, 32,167b, see neurogenesis
-physical activity and, 134, see physical
Ageing , 61,81,96,100,115,120,125,137,141,155b,196b
-AD/Dem and, 43,68,FN#146&251,71,75,78,Chap23A,174b,177b
-cognition, 99,157b,183b,187b
-concept, Chap18,Chap23A
-diseases and, 116
-education and, 126
-healthy and, 126
-population and, 64,71,202b,211b
-successful, see successful aging
Agraphia, 223g
Air pollution, 4,T1&10&16,48,103,118,139,FN#247&327,144,159b,184b
Alexia, 222g
Allele, 4,FN#9,6,11,FN#30,44,46,48,49,92,138,161b,189b,211b,223g,229g
see APoE4, APoE2
Alostatic, 99,222g
Aluminum/ aluminium , 139,141,FN#326,189b,213b,226g
Alzheimer’s disease (AD), 121,222g
-AD syndrome, FN#112,180b,225g, see dementia-AD syndrome
-AD-type dementia, 13,53,FN#49&111,FN#151,179
-beginning, 13,Chap5
-causes, possible, Chap18
-cerebral lesions (neuropathology) and, 28,29
-clinical aspects, Chap13,60,68,72
-concept, 44,FN#140,142,FN#329,143,148b,176b,177b,222g
239

-dementia and, see dementia
-epidemiology/descriptive, 8,FN#23,11, see incidence and prevalence
--analytic, 41,FN#79&80,226g,232g, see RF/PF
-evolution, Chap7,87,90,91,F13,F20,Chap21, see evolution
-family and, 97-99,T9
-Framingham study and, 34
-heredity, 10,Chap4,Chap11,217b
-history, Chap12
-hypothesis, FN#29,78,FN#154&156&159&168&321,191b,192b,198b,208b,222g
-medications/therapy, Chap19, see NPT
-neurodegeneration and, 78, 229
-prevention, Chap3,89,Chap21&22,Chap24,183b
--RF/PF, 1,FN#54,108,115,Chap23F, see RF, PF
-senile, see dementia
-types, fAD (early/familial/monogenetic), sAD (sporadic/late), Chap4&11
-see also fAD, and sAD
Aminoacid, 222g,231g
Amnesia, 222g
-childhood, 103-105,152b,178b,208b,209b,223g
Amyloid
-angiopathy, 28,114
EHWD$ ȕ 10 , FN#29,26-28,43,F16,66,67,78,79,83-85,91,92,142,143,209b,222g,231g
cascade hypothesis, 10,84,FN#157&168&169,173b,174b,208b,222g
Anabolism, 223g
Anomia, 55,61,223g
Anti-amyloid drugs, FN#183, see bapineuzumab, crenezumab, solanezumab
Aphasia , 51,223g,226g
API-ADAD trial, FN#183
ApoE gene/allele , 4,FN#9,11,162b,168b,170b,198b,222g,223g
-ApoE2, 4,FN#9,5,11,138,222g
-ApoE4, FN#9,T1,11,49,53,84,92,FN#183,102,110-112,117,211b,213b,223g
Apoptosis, 18,77,79,105,223g,2309g
APP (Amyloid precursor protein), 10,FN#29,85
Apraxia , 62,223g
Astrocytes , 16,227g
Atrophy
-cerebral, 111
-cortical, 28,115,122,144
-hippocampus, 114,143
Attributable risk, 97,120,232g, see risk
Axon , 16,17,105,128,129,223g,225g,228g,230g
BADL (Basic Activities of Daily Living ), 60,73,223g
Bapineuzumab, 63,84, see anti-amyloid drugs
Beta-amyloid ȕ $ see amyloid beta
Biology of systems (or system biology), 10,12,43,FN#93&169,125,143,180b,215b,223g
-molecular, 125
Biomarkers
-AD, 13,50,71,84,91,114,124,135,164b,175b,193b,222g
-clinical trial and, 67, see trials
240

-CSF, 14,72,84,222g, see CSF
-food, 134, see nutrition
-NFT, 13, see NPT
BMI (Body Mass Index), see obesity
CAIDE study, 111,FN#232,113,213b
Caloric restriction and aging, 125,223g
Case-control study, 113,121,127,224g
-AD risk and, 98,FN#194,112,FN#237
Cases, clinical/pathological, 74,75,106
-AD, 63,72,98
-clinical cases, 1:55; 2:60; 3:73
-dementia, 11,53,63,69
Catabolism, 10,85,224g
Cell reprogramming, 124,FN#258,193b,224g
Centenarians, 123,FN#263,124,149b
Cerebral
-blood flow/vasodilators, 29,52,79,80,157b
-cortex, see cortex
-development, T10
-lesions (mainly AD), 13,28,30,35,115,140
--in memory, 57,58
-reserve, 29,30,32,206b,223g
-pathology and dementias, 115
-structure/s, 20,22
-vascular lesions, 32
CFAS ( Cognitive Function and Ageing Study), 71
CHARGE study, 45
Children , 6,39,46,55,56,60,95,97,98,100-102,105,FN#215&221&327,T10&15&16,133,176b
-CVRF risk, FN#62&287
-MeDi and, 136,FN#315&336,144,196b
-“feral”/wolf/wild, 106,FN#215,182b
-pretangles and, FN#36
Cholesterol, 10,111,FN#309,T14,150b,153b,180b,205b
Cholinergic transmission, 80,81,FN#161&162,F24,142,152b,164b,166b,199b
Chromosome, 156b , 222g,227g,233g
CHSA study, 116,118
Clinical manifestations
AD, Chap13,Chap14
-dementia, Chap15
-MCI, 65,Chap15,
see cases, clinical
Clinical Practice Guidelines (CPG), 88,89,137,224g
Clinical trials, 8,67,90,91,128,150b,161b,173b,225g
-AD preclinical, FN# 83,93
-multidimensional, 92
-primary prevention (AD, dementia), 91,93
-randomized clinical trials (RCT), 6,FN#18,8,42,91,FN#305,224g
-tacrine and, see tacrine
Cochrane Collaboration, 88,89,224g
241

Coffee /quercitin, T1&12&13,139,FN#321,184b,185,192b,195b
-AD/Dem risk/PF, T1,8,121,122,139,FN#321,149,184b
Cognitive /cognition, 69,FN#76,81,90,105,124,156b,163b,172b
-battery, 73,164b,204b
-capacities (or domains), 34,62,76,77,Chap20,89,93,T9,130,224g,229g,234g
-decline/impairments, 7,35,36,37,51,53,56,60,61,Chap15,66,76,80,110,112,120,124,129,131,133,135,140,
153b,161b
-development, 96,FN#196,104-108,112,149b,150b,211b,
-enhancers, 80,81
-enrichment/activity, 107,129,141,144,189b,224g
-examination , 74,77,112,153b
impairment, mild, see MCI
-impairment no dementia (CIND), 116,FN#244,176b
-improvement, 81,FN#180
-normal, 84-87,109,158b
-reserve (CogR), Chap7,42,F15,Chap23B,108,F26,T13,119,144,150b,157b,160b,172b,223g
-stimulation/rehabilitation, Chap20,126,129,151b,159b,179b,225g
-test, 82,93,976,100-102,107
-training, 93,225g
Cohort/s , 225g
-AD/Dem treatment and, Chap 21,Chap22D
-birth cohorts, FN#198&201&222,156b,165b,174b,198b
-children, FN#222&286
-concept, 34,40,225g
-decreasing Dem/AD, 69, T9
-elderly, Chap22E,153b,154b,155b,162b,169b,196b,203b
see eponyms and survey/studies
Complex diseases, 1,5,10-12,Chap10&18,97,99-102,108,188b,225g
Concept/ Definition
-AD, 44,FN#140,142,FN#329,143,148b,176b,177b,223g
-CogR, Chap7,206b,224g
-complex diseases, 77,Chap10,157b
-dementia and, 74,147b,158b,166b,188b,224g
-health and, 78
-intelligence, 229g
-NDD, 85,222g,230g,231g
-preclinical AD, 67,FN#168&178,150b,190b,206b
-predementia/MCI, 61,65,90,114,124,197b,228g
-prevention, 86
-probabilistic diagnosis, 75,224g
-risk factors, Chap10
Cortex/ Cortical
-areas/lobules, 20,23,28,35,36,58,62,83,114,143,225g
-atrophy, 28,115,122,144
-diagram of the CNS functioning, and, 19
-human cerebral cortex , 16-28,F&,102,105,131,170b,196b
-network/processing, 57,62,129
-triune brain and, 20
Cost -effectiveness analysis, 181b,191b,225g
Crenezumab, 92,FN#183, see anti-amyloid drug
CRISPR Cas9, 45,205b
Criteria
242

-AD diagnosis, 72,FN#140,165b
-dementia screening, 118
-probabilistic, 75,225g
-risk factors and, 42
CSF biomarkers
-AB/tau, 67,FN#140&141&151&154,200b
CT (Computed tomography, head scanner), 67,74,94,129
CVD ( Cardiovascular disease/s)
-foetal programming and, 100
-lesion in dementia, 115
-prevention, 34,71,133-135,151b
-risk factors, 40,41,99,T10,111,140, see CVRF
-VaD, see dementia
CVRF (Cardiovascular risk factors), 5,90-94,T10,110-113,FN#252,117
DASH ( Dietary Approach to Stop Hypertension ), 135,FN#312,207b
Definition, see concept
Dementia, Chap8,148b,225g
-AD and, 8,30,Chap8
--syndrome, 53,FN#112&144,76,143,234g
-cognitive (brain) reserve, 29,Chap7, see CogR
-concept, FN#141
-epidemiology, 8,FN#23,11, see prevalence and incidence
-evolution (and AD), 31,F3,Chap7,F13,F20,Chap21
-history, Chap12
-incidence, F2,NF#23&133&246&251&253,T5&8,162b,165b,170b,188b,203b
-predementia o preclinical Dem, 14,35
-presenile, 13,15,52
-prevalence, 39,FN#75
-senile, 4,52,53,73,75.80,81,112,142,148b,158b,179b
-RP/PF, 41,FN#269
-syndrome, 42
-types/causes:
--vascular (VaD), 53,72,75,112,114,121,153b,224g
--others, FN#141&269
Dendrites/ dendritic, 17,18,32,96,105,159b,161b,225g
Depression, 55,56,60,65,73-75,100,103,T11,118
-AD and, 63,140,FN#324,194b
-depressive pseudo-dementia, 73,231g
-RF for sAD, T1&T9-13,121,122,138-140,195b
Diabetes mellitus (DM2), 4
-AD/Dem RF, T1,T12,156b,168b
-chronic/complex diseases, FN#62&98&147&197&200&246&252&310
Diagnostic criteria, 118
-AD pathologic/clinic, 25,FN#48&140,80
-concordance, 75, FN#143&248,159b
-gold standard, 75,FN#140,225g
-probabilistic, 75,225g
DIAN-TU study, FN#183,152b,208b
Diet
-AD/Dem FR/FP, 1,5,7,8,11,12,43,46,50,77,92,94,96,98,T9,100-103,112,113,119,122-4,195b,216b
-healthy, T1&11&12&13&14&16,126,135,FN#200&290&309&312
243

--DASH, 135,FN#312,208b
--MIND diet, 135,FN#132,191b
--MeDi, Chap23E,F30,140,144,145,FN#314&315&336,150b,163b,167b,168,170b,187b,196b,198b,
202b,203b,205b,209b,210b
--PREDIMED, 134,FN#238&310,135,187b,202b
-pyramid, 136,F30,FN#314,150b,210b,218b,219b
Disease/s
-AD (fAD, sAD), see AD
-CVD, see CVD
-chronic (elderly), 10,38,39,FN#77&138,49,77,130,158b,164b,213b,224g,230g,234g
--AD/neurologic, 38,FN#72,77,78,109,153b,157b,168b
--under-diagnosis of, 39,FN#72
-complex, see complex diseases
-infectious, 10,Chap10,FN#77&147&154&155&200,230g,231g,234g
-NCD (Non-communicable), see NCD
-NDD (Neurodegenerative), see NDD
-prion, 230g, see prion diseases
-psychiatric, FN#107&127&128&173,72,73,87,148b,150b,226g,231g
-systemic, see systemic diseases
DNA (Dexosy-ribonucleic acid), 18,102,164b,213b,226g,234g
-brain/neurons and, 45,58
-editing, FN#85
-epigenetic and, 46-49,F16,101,FN#104
-fAD and, see in AD; sAD and, 49, see in AD
-gen/genetic programming, 2,18,227g
-heredity, see heredity
-mitochondrial, 125,229g
-structure, 44,45,FN#88&89
DOHaD ( Development Origins of Health and Dis) , 1,FN#2&198&201,101,218b,226g
Donepezil, 65 , 82,FN#132,90-93,157b,215b
Down syndrome, 85
Drugs
-ACI, see ACI
-anti-amyloid, FN#183
-others, see compound name
DSM ( Diagnostic Statist Manual of Mental Diseases) , 226g
-III, 148b
-IV, FN#140,148b,225g
-V, 65,FN#127,148b,230g
Dysphasia, 55,61,226g
Early life, AD/cognition, FN#250,121,158b,167b,181b,198b,204b,212b,215b
EBM ( Evidence based medicine ), 202b,224b,226g
Edinburgh cohort, FN#222
Ecological survey , 1,FN#2,226g
EDPI ( European Dementia Prevention Initiative ) trial, FN#21,8,92,166b,218b
Education , 48,71,107,108, FN#250,144,150b,162b,193b
-AD/Dem/MCI FR, 2,4,T1,9-11,35,41,T9-12&16,FN#218&222,F16,112,118,FN#252,152b,159b,161b,
165b,172b,178b,179b,184b,189b,191b,200b,201b,204,214b,216b
--prevention, Chap22A,Chap23F,158b
-CogR, Chap7,FN#279&280,Chap22E,189b,224g
Elite survival, 226g
244

EMBASE, 228g
EMEA (European Medicines Agency), 84,224g
EPESE survey, 117,119,166b
Epidemiology/ Epidemiologic, 38,FN#70,158b,164b,168b,174b,177b,183b,199b,201b,207b,208b,224g,226g
-analytic, 41,FN#79&80,226g,232g
-causal pie and, FN#79&82,43,214b
-clinic, FN&79,168b
-concept/definition, FN#70,Chap10,165b,184b
-descriptive, 226g,232g, see prevalence and incidence
-epigenetic, 172b,196b
-over lifetime (whole course of), Chap22E,102,F26,153b,174b,204b
-population-based, Chap9&23,41,113, FN#239,143
-neuroepidemiology, NF#72,149b,152b,192b,208b
-neuropathological, 114
-transition, 41,194b,234g
Epigenetic , 11,12,Chap 4,Chap11,172b,196b
-AD, neurodegeneration and, F16,49,77,147b,182b,186b,187,211b,213b
-complex disease and, 77,167b,197b,208b
-environmental factors, 49,97
-factors, FN#137,77,96,108
-genes-environment interaction, T1,48,125
-intergenerational, 103,167b, see transmission
-mechanisms ( soft inheritance), 2,4,46,F16,190b,212b,213b,226g,227g
-parents and, 48,102,212b
-SN evolution, FN#99,166b,212b
Epistasis , 42,45,49,FN#92,162b,226g
EURODEM , FN#51&319,183b,184b,211b
Evolution
-AD, F3&21,FN#38&48&66&122,157b,166b,168b,177b,222g, see Alzheimer’s disease
--risk, F26
-dementia/MCI, 14, F20&21,FN#126&175,196b
Executive functions, 21,62,100,205b,225g
Exposure , 110,122,171b,226g,232g
-AD/Dem/NND RF, 4,T1,1012,T3,T9,103,T16,FN#200&216,140,161b,208b,213b,216b
Factor/s
-risk factors (RF), see risk
-protective factors (PF), see protective fAD (familial/monogen AD), 3,FN#8&27&29,10-12,Chap 4&11,F11,FN#68&183,49,53,F25,175b,222,234g
Family, 2-4,10,13,60,61,63,72,73,74,81,86,FN#171,89,104,106,109,111,136,142,154b
-AD/Dem prevention, 49,89,Chap22A,142,154b
--RF/PF, T1&9&16,FN#146,97,99,104,106,107,138
-father, 12,92,Chap22A,T9,FN#31&194&215,109,222g
-grandmother, 97,158b
-mother, 1,T1&9&16,12,45,Chap22A&B,FN#31&193&197&211&306,FN#205&216,144,160b,222g,229g
-NPT, 86,91
-SES, 97,98,FN#92&194&196&200&202&&220,107,193b
-stress and, Chap22A
Father, see family
FDA (Food and Drug Administration) , 81,82,84,85,FN#160&163,124,166b,224g
FINGER trial, 92,FN # 194,94,193b,
245

FINMONICA study, 111,FN#232
Foetal/ Fetal, 18,50,181b
-AD/dementia RF/PF, T1&16,109,169b
-Barker hypothesis/DOHaD, 1,FN#2&98&191&197&200,Chap22B,100-103,105,109,152b,156b,169b,
172b,180b,226g
-complex disorders/NCD, FN#4,100,104,143,183b,197b
-hypo/hyper nutrition, 97,101,102,Chap22B
-programing, 100,103,167b,226g
-others, 152b,161b
-weight/size/volume, fetal, 1,29,97,99,100,101,103,104
FOESSA, FN#221,168b
Foods , see nutrition
Frailty/ comorbidity, FN#146&325,119,T13&16,140,156b
Framingham cohort, 8,34,70,110,111,127,130,161b,166b,178b,184b,202b,209b
Free radicals, 124,131,227g,230g
Galantamine , 65,82,83,90,93,157b
Gametes, 48,66,227g
Gen/ Genetic, 2-4,Chap4,18,Chap11,52,78,92,122,142,148b,150b,152b,155b,161b,192b,226g
-AD (fAD, sAD), see AD
--RF/PF of, T1,11,F15,92,FN#183&252,Chap22A,102,F26,T16,159b
-animal models, 81,90
-complex diseases and, 77,188b,225g
-epigenetic (soft inheritance), see epigenetic
-epistasis, see epistasis
-imprinting, 48,FN#154,199b
-inheritance, see heredity
-mechanisms (mono/polygenetic), 2, FN#27&29,77,78,169b,222g,229g
Genome, 227g
-discovery/sequencing, 45,46,176b,212b
-editing, 205b
-GWAS, 49,152b,172b,227g, see GWAS
-Human Genomic Project, 45
-read-write in evolution, 44,204b
Genotype , 117,171b,175b,197b,198b,213b,227g,231g
Glia (neuroglia), 15,18,F4,227g,230g
Global Action against Dementia, 170,218b
Gold standard, 75,FN#140,225g
Grandmother, 97,158b
GWAS, 49, FN#84&101,152b,172b,227g
HAAS ( Honolulu-Asia Aging Study ), 110,FN#229,111,197b
HATICE trial , 92,FN#184,173b,219b
HBP , see hypertension
Health , FN#218&332,F21,144,148b,176b,179b,187b,204b,205b,215b,226g
-AD/Dem/MCI and, T1,T9,FN#214&222,126,T10-12,T15,T16, FN#320&325,157b
-cohorts/studies/trial and, Chap9, see eponyms
-elderly people and, FN#172&182&271,149b,150b,154b,199b,213b,222g
-diet, Chap23E,F21,185b
-physical activity, see PhA
246

-RF/PF chronic diseases, Chapp10,FN#148&226&320,160b,171b,180b,188b,231g
Helsinki ( Helsinki Birth Cohort Study ), 101,198b
Herbs , medicinal, 91,FN#321,
Heredity, 63 , Chap4,Chap11,166b,170b
-AD, see AD and fAD and sAD
-non-mendelian/(epigenetic), 208b, 226g, see epigenetic
-mendelian, 10,229g
-transgenerational, FN#96,172b,176b,196b,208b
Hippocampus, 32,35,36,52,FN#66,105,130,227g,228g
anatomy, Chap6,F9,F10,F13,230g
-atrophy, 67,143
-cognition, 96
-CogR and, FN#57&58
-dementia, F17
-memory, T4,FN#42&48,58,104,105,129,FN#283,131,229g
-sclerosis, FN#53&141,F17
Hisayama cohort, 112,113,FN#233&238,193-195b
Holland cohort ( Dutch Winter Famine Birth Cohor t DWFBC ), 100,101,FN#198
Human Connectome Project, 20,219b174b
Hypertension /HBP, 73,FN#250&312,
-AD/Dem RF, T1,T11,135,155b,214b
-Barker hypothesis, 1,FN#2&98&191&197,Chap22B,100,101,105,151b,156b,172b
-cohort studies and, 111,FN#229&233&240&248&310&312
-complex diseases, 108,111
-modifiable, FN#250,121
IADL ( Instrumental Activities of Daily Living ), 61,62,71,82,22g,227g
Incidence
-concept/definition , 227g,232g
-AD/Dem/MCI, 8,F2,34,40,F23,T5&8,FN#23&72&133&197&246&248&251&253&275&295&321,
129,137,143,149b,155b,161b,161b,165b,170b,173b,177b,183b,188b,191b,198b,200b,202b,203b
-complex illness/NND (elderly), FN#72&309-312&324,147b,153b,158b,169b,206b
Induced pluripotent stem cells (iPSC), 124,224g
Infancy/ infant, 2,30,33, FN#36,Chap22C,128,226g
-AD/Dem RF, T1,46,77,T9,FN#197&209&219&220,101,107,108,T10
-amnesia, FN#213, see childhood amnesia
-complex disorders, FN#4,102,143
-education, 282
-health, FN#218,144
-hyponutrition, FN#202&214,105
-language, FN#215
-neurogenesis, 16,32,147b,
Inheritance, see heredity,
Intelligence , 18,33,41,62,108,144,228g,234g
-AD/Dem risk, 102,T7,FN#286
-CogR, Chap7,FN#59
-education, FN#282
-infantile/childhood, FN#66,144,165b
-IQ, 327g
-psychometric/test, FN#148, 234g
-types (fluid/crystalized), 62,76,228g
247

Intergenerational, see transmission
Kungsholmen study, 70,169b,FN#235
Language , 169b
-AD/Dem/RF, T9,T10,128,FN#334
-aphasia/dysphasia, 107,T10,223g,226g
-bilingualism, 144,156b
-children deprivation, FN#215&216
-cortex/cortex circuit, 21,30,105
-cognition, FN#60&148,61,224g,228g
-development, 104-107,150b,182b
-SES, FN#230,T10
-wild/feral infants, FN#215,182b
Life expectancy, 95,FN#10&123,95,227g
-Spain, F29,206b,219b
Life style, T7
-AD/Dem RF, F15,T16,230g
Limbic (system), F5,23,F13B,35,62
Malignant neuroleptic syndrome, 74
MAPT trial, 92,FN#184,94,160b,212b
MCI, 7,64,T5,118,154b,178b,180b,196b,200b,215b,225g,226g,228g,230g
-case, 2:60
-clinical manifestations, F21,60,64-66,89,116,FN#248,160b,178b,196b,200b,204b,205b,209b
-concept/definition, 13,15,75,FN#40&126-128&241,227g
-CogR, F14
-evolution, F3,64,89,90,FN#248,116,118,131,154b
-etiology, FN#128
-mortality, FN#128&243,118,154b,162b
-neuropathology, 203b
-prevalence, 61,65,F22,118,134
-prevention, 92, FN#180,167b,
-prognostic, 155b,170b,179b
-treatment/therapy, FN#129,66,89-92,FN#175&180&310,&313,T7,135,153b,162b,180b,183b,190b
MeDi (Mediterranean diet), Chap23E,FN#315&336,145,163b,170b,182b,184b,194b,196b
-AD/Dem therapy, FN#309,135,140,187b,203b
-Intangible Cultural Heritage (UNESCO), 137
-MCI prevention/therapy, 168b,187b,203b,210b
-PF, and AD/Dem/MCI/health, T1&16,96,FN#311&313&323,F31,196b,202b,205b,212b,214b
-pyramid, see pyramid
-olive oil, see olive oil
-trials, see PREDIMED, DASH, MIND
MEDLINE , F1, FN#198&222&201&240&247&311,114,219b,228g
Memantine, 66,82,FN#165,87,90,93,157,189b
Memory, Chap 13,Chap20,228g,229g
-autobiographic, 58,186b,210b,228g
-crystalized, 228g
-episodic, 56-59,228g
-explicit (or declarative), 56,57,227g,228g
-immediate (short-term) or primary, FN#119,57,58,73,228g,229g
-implicit, 57,228g,229g
248

-procedural, 57,58,229g
-secondary, long-term, 57,58,81,90,130,151b,204b,229g
-semantic, 57,58,191b,229g
-subjective, 55,56,64-66,153b,229g
Meta-analysis, 120,FN#54&160,131,175b,182b,229g
-AD/Dem RF, 120,149b,150b,156b,151b,182b,185b,195b,197b,206b,203b,216b
-dementia, FN#127,162b,177b,197b
Metabolism , 124,137,142,223g,229g
-neuronal, 10,FN#166&167&269,150b
Microbiota (intestinal flora) , FN#308,133,148b
-Dem/neurologic disorders, FN#306,148b,190b
Microglia , 16
MIND diet, 135,FN#312,191b
MIRAGE study, 172b
Mitochondrio n / mitochondrial, F4,45,47,FN#153&154,201b,208b,229g
MMSE (Mini Mental State Examination), 234g
-dementia diagnosis, 73,FN#141&142
-MMSE-37, 73,118,FN#248,151b
Monongahela Valley study, 116,FN#243,169b,170b
Mother, see family
Mutation, FN#68,175b,197b,211b
Myelinisation, 105,229g
NCD (non-communicable diseases), 1,44,46
-concept, 76,230g
-genetic, FN#94
-fetal/infancy risk and, FN#197&200&202&214
--other risk, FN#290#310&335
-SES, FN#220
-United Nation, FN#320
NCD Risk Factor Collaboration, 192b
NDD (Neurodegenerative disorders), 45,53,96,142,154b,176b
-concept, 77,78,FN#151-153,157b,168b,173b,177b,213b,230g
-epigenetic, FN#96&99
-RF/PF, FN#200,FN#269,FN#326,167b,208b
-SES, FN#220
-types, 47, FN#141,159b,233g
-underdiagnose, FN#72
NEDICES cohort, 33,39,60,154b,171b,190b,219b
-AD/Dem, FN#75&239,F22&28,155b,162b,204b,212b
--RF, T13,FN#248&294&295,153b,185b
-aging, FN#239
-CogR, FN#58,
-MCI, FN#72&248,155b,162b
-NDD (PD, essential tremor), FN#248,154b,190b,197b,202b
Nervous system (NS), Chap6
-central, Chap6,229g
-peripheral, 229g
Networks, 168b
-neural/neurons, 17,19,229g
--CogR, 207b,224g
249

--memory and, 57,58,Chap7,104
-synapsis, 30,128,129,233g
Neural plasticity, 230g
-AD, 189b
-aging and, FN#146&269,
-synaptic and memory, 148b
Neurites, dystrophic, 26,26,230g,232g
Neuritic plaque (NP), see plaque
Neuroanatomy, Chap6,185b,192b
Neurocognitive disorder (DSM-V), 148b,226g
-major (dementia), 148b,226g,230g
-mild (or minor), 65,FN#127,148b,184b,230g, see MCI
Neurodegeneration, Chap18,230g
-AD, FN#151,217b
-epidemiology, 188b,198b
Neurofibrils , 230
-AD, 147b,161b,171,189b,194b,197b
see NFD and NFD (neurofibrillary tangles)
-threads, 26,29,52,F18,142
Neurogenesis , 22,131,147b,172b,174b,230g
-adult, FN&58,154b,189b,190b
-infancy, 16,FN#42
Neuroimaging
-AD, FN#67&68&138-140&240&331
-CogR/education, FN#280
-dementia, FN#141,240
Neuroleptics , 63,FN#142230g,233g
Neuron / neuronal, 47
-anatomy/physiology, F4,Chap6
-CogR, 29,30,32
-damage/lesion,
--AD,NDD,10,T2,77-79,FN#154&162,83,FN#183
--specific, see NFT, tau
-mechanism, aging, FN#269
-number, FN#42,32
Neuropathology , FN#134,153b,174b
-AD/Dem, F11,78,FN#151,192b,203b,210b
Neuropil , T2,83,230g,232g
Neurotransmission , 16,19,81,F24,227b,230g
Neurotransmitters , 81,230g,233g
Neurotubules, F12,FN#45,83,230g,233g
NFT, see tangle
NHANES ( (National Health and Nutrition Examination), FN#71&291,168b,193b,219b
NIA (National Institute on Aging, US) , 116,FN#242
NICE (National Institute for Clinical Excellence, UK) , 88,FN#173&141&290,103b,219b
NIH (National Institute of Health), 7,13,FN#72&111,162b,222g,228g
NINCDS-ADRDA , AD diagnostic criteria, FN#140
NPT (Non-pharmacological trial) in AD/Dem, FN#170-175,T6,86-89
Nun study, FN#63,191b,205b
Nutrition / malnutrition, 1,8,48,96,97,F26,T16,156b,164b,165b,180b,206b,210b,220b
250

-AD/Dem/NCD RF, T1,90,92,100,T9&10,FN#218&245&320&333,145,175b,178b
-hypo-nutrition, FN#2&197&200&214,T9&10,T16,101, see Barker hypothesis
-hyper-nutrition, FN#208,T9&T10&T16
-maternal/infancy RF, 1,T1,T9&10,100,FN#200, 156b,165b
-pyramids, 136,F30,FN#314,150b,210b,218b,219b
-social conditioning, FN#187&188
-superfoods, 137, FN#317,218b
-supplementary foods, 13,97,FN#307&317,194b,207b
Obesity (high BMI), FN#287&290,160b,225g,230g,235g
-AD/Dem RF, T1&10-12,12,Chap10,F26,T16,153b,197b
-mortality, FN#62
-FR chronic dis, 34,40,76,FN#147&200&214&250&310&335,102,131
OECD (Organization for Economic
Cooperation and Development), FN#259,194b,219b
Olive oil, FN#312&317&323,134,136,200b,207b
Optogenetic , 50,161b
OR (“Odds ratio”), T13,232g
Oxidative stress,10,47,84,114,125,FN#267&269,131,227g,230g
Paired helical filaments (PHF), F12,230g,231g
PAQUID cohort, FN#64&247,118,149b
PET (Positron emission topography), 3,32,FN#67&140,84,128b,222g
-
$ ȕ LQ
-tau, FN#67,177b
Phenotype, 46,96,157b,166b,177b,226g
-concept, 231g
-p henotype thrifty hypothesis, see thrifty
-thrifty phenotype, FN#191
Physical activity, 4-6,30,35,Chap23D,139,176b
-Concept/definition, Chap23D
-AD/Dem/cognition, 131,149b,158b,159b,160b,162b,172b,174b,185b
--RF/RP, F15,141,183b,197b,199b,201b,203b,206b
-clinical trial and, 93,94,112,118,212b
-health/mortality, 131,133,144,159b,168b,175b,181b,190b,202b,204b
-sedentary habit, 121
-US Dpt. Health/WHO, 132,210b,214b
Plaques
-senile (PS), 10,13,F11,F12B,T2,29,36,52,66,74,78,83,142,161b,179b,189b,203b,232g
-neuritic (PN), Chap6,F11,T2,F12B,232g
Plausibility, biological, 42,F15,3,70,89120,140,231g
Polypeptide, 10,83,84,222g,231g
Poverty, see SES, low
PREDIMED trial,113,134,FN#310,135,184b,202b preDIVA trial, 92,94,211b
Prefrontal, lobule/areas, 21,F8,F13,T4,105,108,169b,231g
Pregnancy , 97,98 , Chap22B,144,FN#333
-AD RF/PF, T1,T10&16,151b,177b,218b
Pretangles , 13,27,36,143,231g
Prevalence
251

-concept/definition , 227g,232g
-AD/Dem/MCI, 4,8,65,FN#14&25&51&72&75&133&246&248&249&252&253,F23,T5
-others disorders, FN#72&265,F22,122
see Alzheimer disease, dementia, MCI, cognitive
Prevention AD, Chap21&22&24
-AD/Dem/MCI RF/PF, see risk and preventive
-primary, T8
Priming , T4,229g
Prion diseases, 230g
-AD, PD and, FN#152, 171b,212b,213b
-Creutzfeldt-Jakob disease, 78
-Prion-like transmission, 230g
proteinaceous nucleating particles, 78
Prosopagnosia , 62,231g
Prospective study, 2,FN#18,39,40,149,150b,171b,225g
-AD/Dem, 161b,163b,164b,166b,173b,184b,185b,187b,194b,205b
-MCI, 162b,206b,209b,214b
see cohorts
Proteasome , 47,F16,191b,231g
Protective / tion factor (PF), Chap10,FN#334,160b,189b,202b,231g
-AD/Dem/MCI, Chap23&23F,T1&11-13&16,120,FN#18&84&250&322,F31,147b,184b,185b,223g
Pseudodementia , 73,231g
Radicals, free, 131,FN#267,227g,229g
Relative risk (RR), 120,FN#252,T12
REST factor, FN#269
Review , 1,2,FN#130&157&161&179&239&250&171&172&316&318&321
-AD/Dem/MCI, 131, FN#292,156b,160b,162b,167b,176b,179b,193b,197b,199b,201b,204b,213b
--RF/, 120,127,128,FN#277&292&231,139,149,N#324,150b,153b,163b,165b,180b,185b,195b,197b
--therapy/NPT/prevention, FN#171&175&176,150b,157,159b,160b,161b,189b,194b,206b
-systematic, 81,86-88,90,FN#292,160b,164b,168b,169b,174b,175b,176,181b,189b,196b,210b,224g,226b,233b
Risk factors (RF), 1,4,11,34,41,91,FN#200&218&232&252,96,134,Chap23F,144
-AD/Dem/MCI RF, T1&3&9&11-13&16,FN#200,F26,153b, see Alzheimer’s dis, dementia and MCI RF
Rivastigmine , 65 , 82,FN#164,F24,90,T7,157b
RMI/ RMIf, F8,32,36,55,67,84,108,128,FN#45&67&119&140&141&279,181b,222g
RNA (Ribonucleic acid), 47,48,F16,226g,229g,232g,233g
-miRNA, 48,49,F16,164b,170b,179,211b,216b,232g
Rotterdam cohort, T5,113,FN#101&240&324,164b,174b,175b,176b,189b,195b,203b sAD (sporadic/late), 3-10,T1,14,Chap4&11,43,49,50,67,71,74,75-78,80,85,89-4,175b, 222g
--hypothesis, 84,101,102
Saliva biomarkers, 49,FN#104,155b,160b
Screening , 114,118,FN#248,151,197b,212b,227b,232g
Senescence , 5,125,126,130,137,143,175b,232g
Senile dementia, 53,75,76,80,81,111,112,142,158b,179
Senile plaque (SP), Chap6,232g
Sensitivity , FN#140,232g
SES (socioeconomic status), F23,96,97,107,108,129,158b,162b,178b,190b,210b,215b
-AD/Dem/MCI/ RF, T1&9&10&16,201b
252

-brain development/disorders, FN#194&196&220&222&283,167b,172b,198b
-low (poverty)
-variables/disparities, 33,FN#180&187&188&282,159b
Sirtuins , 125
Sleep , 63,140,T16,153b
Social , 21,58,72,74,75,80,FN#17&158&187&188&218&235&282,Chap22,104,T10&11,119,140,144,148b,
162b,173b,187b,206b,218b,225g
-isolation/integration, 33,123,T16
-SES, see SES
Solanezumab , see A4, 84,92,166b,169b,175b,204b
Specificity , T3,FN#140&142,232g
SPECT , 36,67
Sporadic AD, see sAD
Statins, T4,153b,188b,202b
Stimulation cognitive, see training
Sedentary , T1&13,FN#287,Chap23D,169b, see physical activity
Successful aging, FN#148,T14,126,156b,165b,189b,222g
-cognitive aging, FN#265,127,155b,170b,172b,200b,217b
Survey /study, Chap9,98,FN#27&30&49&53&65&78&84&111&113&141&123&154&165&171&172
FN#194&186&197&215&220&235&243&245&246&251&253&275&313&315&324,T14,160b,193b,233g
-long duration, T5,FN#290&293,F28
see eponyms
Synapsis/ synaptic, 17-19,30,85,122,148b,183b,230g,233g
-loss, 29,78,83,142,208b
-networks (connections), 16,17,18,128,129,224g
-presynaptic proteins, 32,FN#279,128,174b
Syndrome , 30,42,73,FN#142,178,159b,201,202b,224,225g,228g,231g,233g
see eponyms
Synuclein RU Į
-synuclein), 78,171b,233g
Systematic review, see review systematic
Systemic diseases, 44,72,74,78,T11&16,114,140
-AD as, 190b,216b
-AD/Dem risk, T11&13&16
-DOHaD and, 141
see illness denominations and NCD
Tacrine , 65 , 81,FN#163&164,82,164b
Tangle (Neurofibrillary, or NFT), 10,Chap6,F12,F18,T2,47,Chap12,171b,176b,189b,197b,203b,233g
Tau , Chap6,F16,67,84,92,FN#140&141&151&152&154,F24,140&323,171b,176b,177b,190b,205b,231g,233g
-anti-tau vaccination/therapies, FN#166&183,195b
-CSF in, see CSF
-tauists, 209b
-tauopathy, FN#154&233,163b,177b,233g
TDP-43 (TAR DNA-Binding Protein 43), 28,115,168,192b,233g
Tea , 91,128,FN#312&321,195b
Telomere , FN#328 , 124,151b,156b,170b,233g
-telomerase, 124,156b,233g
Test , cognitive, 56,93,103,108,FN#139&164,222&141-2,228g,234g
Thrifty hypothesis, 46,FN#98,96,172b,231g
-foetal syndrome, 101
253

Tobacco , 1,T1,8,9,40,46,71,T9&10&13&16,103,FN#200&229&250,144,151b,232g
Toxic / toxicity, FN#154&187&188&200&320&326,166b,172b,186b,222g,224g,226b,227b
Training / stimulation, 225g
cognitive, FN#18,86,T6-8,FN#172&173&176&178,89,129,151b,153b,161b,193b,195b,199b,215g
-others, T6-8,7,91
Transgenic (mouse), FN#58&323&167,140,234g
Transition, epidemiological, 41,194b
Transmission, intergenerational, 2,97,FN#192,100,103,234g
Trauma
-cranial/brain, T1,32,33,FN#50&328,T16,F31,151b,184b
-psychological, 107
Treatment / therapy, 38,FN#76,66,73,144,147b,148b,157b,160b,152b,162b,180b,212b,215b
-non-pharmacologic, Chap20, see NPT
-pharmacologic, Chap19,FN#157&160&163&167&171&267&327
TREML 2 , gene, FN#84,153b
Trials , 224g,226g,229g, see clinical trial
-AD/Dem prevent, 8,T7&9,FN#21&290&307,67,Chap19&Chap21&Chap23,149b,172b
-long duration, FN#290
see eponyms and its bibliography references
TV , 61,103,130,FN#216&287&289&316,144,227g
Twins , 11,112,127,FN#272,155b
UNICEF, FN #200,105210b,220b
Uppsala cohort, 112,FN#101&235,168b
USDA ( U.S. Department of Agriculture ), FN#314,186,220b
US (Department of Health and Human Services), 188b,193b,210b,219b
Vaccine
-AD, or anti-
$ ȕ G rugs, 43,83,143,186b
-anti tau, FN#166,195b
-new vaccines, 92
Validation therapy, 87,89,220b,234g
Variable , 33,42,65,77,137,223g,234g
Vascular disorders, see CVD and CVRF
Verbal fluidity, 234
Vitamins , 8,FN#20,74,75,91,T7&16,118,138,139
WAIS ( Wechsler Adult Intelligence Scale )
-intelligence and, 228g
see cognitive
-test, 33,56,62,227g
Whipple disease, 74
Whitehall II cohort, FN#52,112,FN#234,187b,205b
White collar and blue-collar workers, 234g
White (matter) or subcortical substance, 111,114,143,234g
WHO ( World Health Organization), 3,73,157b,187b
-Age Associated Dementia-SPRA, FN#246
-dementia risk reduction, 118,FN#250,157b, 214b,215b
254

-initial period of life and, 108,157b, 214b,214b
-MONICA study, 111
-NEDICES cohort, 118
-NCD and, 73,214b
-physical activity, 130,FN#290,132,144,214b
Women’s Health Study, FN#312,185b
Yoga, T7
Yoruba, etnia, 117,FN#246,170b,173b
ZARADEMP cohort, 70,118,119,FN#249,185b
Zones, blue, 123,FN#263,158b
255