SUPPLEMENTATION AND ALZHEIMER’S DISEASE:
A PRACTICAL APPROACH
PART 1
By
Sarah Pigozzo
Nutritionist
1
THE DISEASE
Alzheimer’s Disease (AD) is one of the most challenging and prevalent neurodegenerative
disorders at present. About 50 million people around the world live with AD and it has become a
global health concern due to its devastating impact on individuals, families, and the entire
society.
The disease was described in 1907 by Alois Alzheimer as a form of presenile dementia, due to
the fact that his first patient was 51 years of age when the symptoms appeared1.
AD is characterized by an irreversible deterioration of intellect, memory, cognition, behaviour,
and emotion. Memory failure, especially recent memory, is usually the major symptom in the
early phases. Over time memory loss becomes more pronounced2 and changes in behaviour,
such as irritability, mood swings, and social withdrawal may appear3,4. The disease lasts an
average of about seven years with continuous deterioration, in the final stages, with the patient
losing any ability to talk, think, or move, and receding to an infantile behavioural state5. Although
AD can occur in any age group, the disease affects mainly elderly people, usually after 506. After
the age of 65, the risk of acquiring it doubles every five years. Due to their longer lifespan
expectancy, women comprise about two-thirds of the Alzheimer’s patient population, even
though AD does not seem to be gender specific7.
The exact cause of AD is still not completely clear, although it seems to be a combination of
genetic, environmental, and lifestyle factors.
PATHOGENESIS
AD is classified as familial (Early Onset AD, EOAD) or sporadic (Late Onset AD, LOAD) based on
its occurrence, both forms showing high heritability.
Both EOAD and LOAD have a similar pathogenesis, still not yet fully understood, with two distinct
types of aggregates (beta-amyloid plaques and neurofibrillary tangles) which are the primary
neuropathological indicators of AD8. It has been found that several key mechanisms are
important in the development and progression of the disease. Here are some of the main factors
involved in the pathogenesis of AD:
- Beta-amyloid plaques: The formation of beta-amyloid plaques is one of the main features of
AD. Beta-amyloid (Aβ) is a protein that gathers in the brain to form insoluble aggregates called
amyloid plaques. These plaques can cause inflammation because they interfere in the
communication between brain cells.
- Neurofibrillary tangles: Neurofibrillary tangles (NFT) are abnormal accumulations of a protein
called Tau inside nerve cells. Tau is involved in stabilizing microtubules, important for the
structural support of nerve cells. Tau becomes abnormally modified in AD and forms tangles,
damaging nerve cells and interfering with their function.
2
- Inflammation: The immune system of the brain can be activated in response to Aβ and other
factors, leading to the production of inflammatory cytokines and an inflammatory response.
Chronic inflammation can further damage brain cells.
- Oxidative stress: Aβ plaques plus inflammation can lead to an increased oxidative stress in
the brain. Oxidative stress, which occurs when there is an imbalance between the production of
free radicals and antioxidant defence mechanisms, can cause brain cell damage and contribute
to AD progression.
- Synaptic dysfunction: The loss of synapses is another important feature in AD pathogenesis.
The presence of Aβ plaques and NFT can interfere with synaptic transmission, impairing
communication between nerve cells and causing progressive loss of cognitive function7.
These are just some of the main mechanisms identified in the pathogenesis of AD. The disease
is complex and involves many other factors that require further research for a complete
understanding.
MOST COMMON NON-GENETIC FACTORS
Almost 70% of the chance of developing AD is due to genetic factors. However, several other
risk factors may contribute to the development of the disease. These include:
-
aging, seemingly the most important risk factor of AD (“the neurobiology of aging and AD
are walking down the same road”)8
-
cerebral vascular abnormalities (such as haemorrhagic infarcts, vasculopathy, subdural
hematomas, and mild to severe ischemic cortical infarcts), chronic central nervous system
(CNS) infections, frontal and temporal lobe solid tumours, a history of head injuries
-
cardiovascular diseases (i.e. hypertension, insulin resistance9, diabetes, and high
cholesterol) or chronic pulmonary (as they can impair cognitive function by reducing
oxygen perfusion to the brain)
-
obesity, lack of physical exercise, smoking10
-
low educational attainment,
-
oxidative pressure,
-
drug intoxications, heavy metal poisoning, pollution exposure,
-
fluid and electrolyte imbalance,
-
endocrine-metabolic disorders (e.g., hyperthyroidism, hypothyroidism9, hypoglycemia,
Cushing's disease, chronic hepatic encephalopathy, azotemia),
-
vitamin deficiency, in particular Vitamin D9
-
depression, chronic stress or sleep abnormalities7.
3
Fig.1. Different risk factors attributed to AD development7
DIAGNOSIS
Due to the fact that amyloid accumulation in the brain begins more than two decades before
cognitive decline, an early diagnosis at the preclinical stages of AD is an important issue. The
AD related cognitive decline has several steps:
Chronic stress
subjective cognitive decline (SCD)
mild cognitive impairment (MCI)
AD
dementia
Reversing AD dementia is not yet possible. MCI, instead, can be reverted to the normal condition.
A very early diagnosis may facilitate preventive pharmacological and nonpharmacological
treatments before the manifestation of dementia.
Due to the complexity of AD, the research and validation of standard clinical diagnostic
biomarkers is not easy8. Biomarkers, like Aβ and tau proteins, in cerebrospinal liquid,
neuroimaging procedures, and some blood-based biomarkers are already available but they are
either economically unsustainable or invasive. New diagnostic tests that can detect AD at an
early stage with high specificity at relatively low cost, are highly necessary. Modern analytical
diagnostic tools can determine, with high specificity, several biomarkers of AD in the blood, such
as pathogenic proteins, markers of synaptic dysfunction and markers of inflammation. There is
a considerable potential in using microRNA (miRNA) as markers of AD. Diagnostic studies based
on miRNA panels suggest that AD could potentially be determined with high accuracy for
individual patients. Furthermore improved methods of visualization of the fundus of the retina,
that can detect particular AD related features, are showing promising results for the potential
diagnosis of the disease11.
4
TREATMENTS AND FUTURE PERSPECTIVE
Unfortunately there is no cure for AD. However the understanding of its causes and risk factors
is vital in identifying potential preventive measures and developing effective treatments.
Available treatments include strategies to manage symptoms, slow down progression, and
improve the quality of life for affected individuals. They can be divided into two main groups of
intervention:
-
pharmacological treatments: usually involving cholinesterase inhibitors (which inhibit
breakdown of acetylcholine, a neurotransmitter involved in memory and cognitive
processes) which can temporarily alleviate cognitive symptoms, and N-methyl-Daspartate (NMDA) receptor bad guys (which regulate brain levels of glutamate and
manage AD symptoms),
-
non-pharmacological approaches: inter alia cognitive stimulation (puzzles, memory
games, and reminiscence therapy), physical exercise (improving overall health, reducing
cognitive decline risk, and enhancing mood and well-being), social activities (i.e.
meaningful activities, such as art or music therapy, which can have positive effects
promoting emotional connections and reducing behavioural symptoms) and dietary
modifications.
Promising research includes immunotherapies targeting Aβ plaques and tau protein, and new
drugs aimed at reducing neuroinflammation and oxidative stress.
Researchers are also focusing on anti-inflammatory and immune-modulating therapies to
mitigate the inflammatory response in the brain and potentially slow down disease progression.
Studies are also looking into the gut-brain axis and the role of the microbiota in AD. Recent
evidence highlights the potential role that gut microbiota (GM) may have in the modulation of
neuroimmune functions beyond the gastrointestinal tract through the brain-gut axis. Research
on GM-brain interactions suggests that GM has a key role in regulating microglial maturation and
activation in homeostatic conditions.
Prevention strategies are a key factor in AD research. Lifestyle interventions, promoting physical
exercise, maintaining a healthy diet, engaging in cognitive and meaningful social activities and
managing cardiovascular risk factors, are being studied for their potential in reducing the risk of
cognitive decline and AD. Population-based studies on modifiable risk factors and the impact of
education and socioeconomic status on cognitive health, are providing insights into preventive
measures that can be implemented on a broader scale12.
5
PREVENTING OR DELAYING AD
While no definitive prevention method currently exists, several supplements have been studied
for their potential benefits in the prevention of AD. It is important to note that these supplements
should not be considered a substitute for medical advice, and consulting with a healthcare
professional is always recommended before starting any supplementation regimen.
As previously said oxidative stress can cause brain cell damage and contribute to the progression
of AD, therefore supplementing strong antioxidant, e.g. alpha-lipoic acid (ALA), has shown
interesting
results.
Among
the
multitude
of
vitamins
and
supplements,
vitamin
D
supplementation in deficiency states and curcumin consumption have demonstrated modest
benefits with relation to cognitive performances13.
Many studies have been focusing on different diets and their impact on AD (prevention or delay)
Strong evidence indicates an association between high adherence to the Mediterranean Diet
(MeDi) and prevention of AD. Reseach on Mediterranean–DASH Intervention for Neurocognitive
Delay (MIND) diet and MeDi diet have shown that MIND could be potentially more beneficial than
MeDi (but long-term controlled trials are necessary).
Since research has revealed that neuropathological changes in AD begin years before the
appearance of symptoms, it would be smart to adopt some “brain healthy” dietary practices early
in life to deter the incidence of AD in later life13.
The aim of this work is to discuss certain supplements that have been studied for their potential
role in AD prevention and/or delay, focusing on the ones most commonly used, easily available
to the general consumer, and known to be safe/well tolerated. A practical review, if you wish, on
supplements and nutritional indications that could be beneficial in preventing or slowing down
the onset of the disease.
ALPHA-LIPOIC ACID
The enhanced degree of oxidized peptides, progressive glycosylation products and by-products
of lipid peroxidation, is the proof of the involvement of oxidative stress in AD. The equilibrium of
antioxidant enzymes has a critical role in antioxidant defence mechanisms as opposed to injury
caused by reactive oxygen species (ROS). ROS has been proven to cause neuronal injury in aged
and AD individuals. Indeed, the accumulation of Aß induced by ROS in AD patients accounts for
lysosomal degradation and eventually leads to neuronal death. Alpha-lipoic acid (ALA), which is
naturally present in food, has many important functions thus being proposed as a neuroprotective
agent for the treatment of neurodegeneration14. Some of those properties are:
-
Antioxidizing:
ALA is a quite strong antioxidizing agent due to its capability to penetrate the brain blood barrier
(BBB) consequently promising to be a suitable agent in the therapeutic approach to AD. ALA is
also known as “universal antioxidant” thanks to its free radical scavenging properties. The most
important and widely occurring antioxidant naturally present in the brain is reduced glutathione
(GSH) which neutralizes the cytotoxic activity of extracellular ROS which, together with
6
hydrogenperoxide, is a byproduct of common biological pathways. AD-related depletion in
glutathione levels has been reported in AD models. Therefore there are growing considerations
regarding the role of glutathione in AD. ALA has been shown to upregulate glutathione expression
in animal models15,16.
-
metal chelating:
an imbalance in the equilibrium of metal ions, e.g. Zinc (Zn), Copper (Cu), and Iron (Fe), could
potentially lead to abnormal metal-Aß interaction in AD. Aberrant levels of Fe in neurons have
been reported in multiple neurodegenerative conditions, such as Parkinson's disease (PD) and
AD. It has been shown the colocalization of Fe and Aß deposits. ALA, as a metal chelator, could
decrease the concentration of iron that impairs neurons and it also downregulates the active iron
pool in neuronal cells by upregulating iron reserves. It has been proposed that ALA, acting on
Fe, could induce the solubilization of Aß plaques and decrease amyloid aggregation in AD patients
.
14,16
-
Glioprotective:
The involvement of neuroinflammation induced by microglia and astrocytes in AD is supported
by various preclinical and clinical data. Microglia are the resident macrophages of the brain which
get activated into disease-associated microglia (DAM) under inflammatory or neurodegenerative
conditions. Activated microglia can potentially cause neurotoxicity and catalyse the progression
of neurodegenerative disease. Some studies have shown that ALA reduces reactive astrogliosis17.
-
Glucose metabolism (uptake) regulator:
Glucose hypometabolism is one of the crucial factors in AD pathogenesis. ALA is also involved in
the induction of glucose uptake. Experimental studies show that the concentration of glucose
transporters in chronic AD patients’ brain is decreased. ALA improves glucose metabolism
impairment in various metabolic syndromes. Studies on AD models have shown that 10 mg/kg
of ALA can remarkably increase the level of the neural glucose transporters (both mRNA and
peptides) thus indicating that it could restore glucose metabolism in neuronal cells.
-
Mitochondrial dysfunctions preventer:
Mitochondrial dysfunctions could be implicated in cerebral aging and neurodegenerative
conditions, e.g. AD and PD. Loss of mitochondrial activities includes an impairment of the ATPconverting complexes partially due to oxidative stress. The activities of ALA in reversing the agelinked cognitive decline include upregulation of cofactors of enzymes in impaired mitochondria.
-
anti-inflammatory:
ALA's anti-inflammatory activity is caused by multiple mechanisms. It can suppress the activation
of NF-κB, a transcription factor that plays a key role in initiating/regulating inflammation. By
inhibiting NF-κB, ALA reduces the production of pro-inflammatory cytokines and other
inflammatory mediators. ALA also modulates
cellular
signalling pathways involved in
inflammation. Furthermore it activates adenosine monophosphate-activated protein kinase
(AMPK), a protein that regulates energy metabolism and has anti-inflammatory effects.
7
The activation of AMPK by ALA inhibits the production of pro-inflammatory molecules and reduces
the inflammatory response. Moreover ALA can enhance the activity of antioxidant enzymes
helping the reduction of oxidative stress and inflammation. ALA contributes to the regulation of
inflammatory processes thanks to the increase of the levels of these enzymes. In addition, ALA
shows immunomodulatory effects, which influences the activity of the immune cells involved in
inflammation. It can also lead to a balanced immune response and decreased inflammation by
modulating the function of macrophages and T cells, 14,16.
Fig. 2: Alpha-lipoic acid can improve cognitive performance and could be considered as a preventive treatment for AD
by affecting multiple mechanisms such as: (1) impaired acetylcholine production; (2) metal toxicity; (3) impaired glucose
uptake; (4) radical formation, ROS production, neuroinflammation; (5) impaired amyloid plaque formation; (6) decreases
glutathione expression; (7) impaired neurotransmitter levels.14
CURCUMIN
Curcuma longa, usually known as turmeric, is a perennial herb member of the ginger family, with
133 different species available around the world. Turmeric is generally referred to as “golden
spice” or “spice of life”. It is used as a cooking spice, cosmetic/dying agent and also in medicine
to treat several disturbs, such as skin infections and liver and gastrointestinal disorders. Several
studies demonstrate therapeutic contributions of curcumin in many neurological diseases. Lower
incidence rate of many neurodegenerative diseases in Indians could be attributed to the regular
intake of turmeric in their diet. Curcumin has been proven to show antioxidant, antiinflammatory, anti-cancer and antimicrobial activities, and has therefore obtained global
recognition. It is used in the treatment of diabetes, arthritis and hepatic, renal, and
cardiovascular diseases 18.
Curcumin
directly
binds
to
misfolded
proteins,
limiting
their
aggregation,
in
many
neurodegenerative diseases. It also maintains homeostasis of the inflammatory system and
enhances the clearance of toxic aggregates from the brain, scavenges free radicals, chelates iron,
and induces anti-oxidant response elements. Besides correcting the dysregulation of several
pathways, curcumin may have multiple effects via a few molecular targets. Curcumin is a drug
8
of interest in the management of various neurodegenerative disorders. 19 Clinical trials conducted
so far on curcumin have confirmed its therapeutic potential in the treatment of various
neurodegenerative diseases 20 (Figure 3).
Fig. 3: A summary of molecular mechanism of action of curcumin in different neurodegenerative diseases19
Curcumin, thanks to its strong anti-inflammatory activity, binds with Aβ thus preventing protein
aggregation, reducing the progression of neuronal damage in AD brains. Another important
mechanism in AD pathogenesis is the formation of reactive oxygen species. Curcumin has a
strong antioxidant and free radical scavenging activity. It inhibits lipid peroxidation which reduces
amyloid accumulation and oxidative stress-mediated neurotoxicity19. Oxidative stress increases
the concentration of metals, e.g. Cu, Zn, Fe, in the brain. Curcumin also suppresses the activity
of several transcription factors (enhancer) that lead to further production of Aβ21.
Studies of animal models (mostly mice or rats) show great potential in preventing memory loss,
restoring cerebral flow, reducing oxidative stress and decreasing Tau protein phosphorylation.
Regarding human data, a few randomized clinical trials (RCT) have been performed measuring
the effects of curcuminoid administration on cognitive functioning. Most of these trials included
elderly people, with or without AD20. One of the most interesting results was collected by Dr.
Small in 2018 when, in a RCT, his group measured the effect of 90 mg of curcumin administration
twice a day for 18 months. Visual and verbal short-term memory, as well as attention, improved
in the treated group when compared to the placebo group. They also found a reduction in Aß and
tau accumulation in the amygdala with stable levels in the hypothalamus in the curcumin treated
group compared to the elevated levels in the placebo group22. Further studies are needed to
asses safety dosage (some mild gastrointestinal issues have been reported).
Poor solubility and bioavailability of curcumin strongly affects its therapeutic application. Various
strategies have been employed to increase its bioavailability. Nanotechnology has been used to
prepare nanoformulations of curcumin, improving its solubility and bioavailability. Usage of these
9
compounds in animal model has shown great potential and further research should focus on
testing their potential on humans.
VITAMIN D
Vitamin D (Vit D) is a fat-soluble steroid vitamin, discovered in the late 1800s when England was
suffering an epidemic of rickets, caused by reduced calcium levels related to Vit D deficiency. In
the early 1920s they discovered that fish oil with a high level of Vit D could have been used to
treat rickets in population23. Vit D deficiency still exists all around the world, with half of its
population lacking Vit D in different degrees and more than 1 billion people suffering from Vit D
deficiency24. Even more important are the subsequent findings that suggest that Vit D deficiency
is related to many other human diseases, such as neurodegenerative diseases, i.e. inter alia AD,
PD, multiple sclerosis (MS) and vascular dementia (VaD), as well as cancer, cardiovascular
diseases, immunity diseases, etc.
Vit D can be turned into a hormone in vivo with genomic and non-genomic actions, bringing on
several physiological effects25. It regulates the expression of almost 900 genes, including the
regulation of calcium and phosphate metabolism, immune response, and brain development23.
Vit D promotes the absorption of calcium and phosphorus, keeping calcium homeostasis in order
for proper mineralization of bone tissue. Vit D also plays an important role in the immune system.
It strengthens the antimicrobial effects by increasing the chemotaxis and phagocytic capabilities
of innate immune cells and the transcription of their antimicrobial peptides. In macrophages or
monocytes, Vit D induces the production of antibiotic peptides25.
Vit D also regulates the differentiation, proliferation of neurons and microglia, and dopamine
signaling transduction. Vit D has an important role in brain development and synaptic plasticity,
thanks to its proven effects in regulating synaptic plasticity and molecular transport in cell
organelles, and maintaining cytoskeleton26. It also restores calcium homeostasis and reduces
apoptosis and neuronal death. Furthermore, Vit D sustains mitochondrial functions thus reducing
the formation of ROS and regulating the expression of antioxidants. Vit D also controls the
synthesis of many neurotransmitters. Other functions of Vit D, inter alia inhibiting inflammation
and the proliferation of smooth muscle cells, may also be involved in cardiovascular and
neurodegenerative diseases. In various types of cancer, Vit D has been proven to exert its effects
through inhibition of proliferation, inflammation, angiogenesis, invasion, metastasis, induction of
differentiation, and promotion of cell apoptosis25.
Vit D also plays a key role in ageing. There is increasing evidence that ageing is not a single
process; it seems to be driven by a number of cellular processes such as autophagy,
mitochondrial dysfunction, inflammation, oxidative stress, epigenetic changes, epigenetics and
DNA disorders (including telomere shortening, which act to drive the processes of ageing) and
alterations in Ca2+ and ROS signalling. All these processes are regulated by Vit D (Fig.4).
An important role in the ageing process is played in the genome by epigenetic changes, the more
important of which is DNA and histone methylation, which have great influence on the expression
of most of the genes responsible for healthy ageing. In fact epigenetic changes have been linked
to oxidative stress. Vit D represents one of the major regulators of antioxidant expression and
appears to control the epigenetic landscape of its multiple gene promoters27.
10
Fig. 4. The Vit D hypothesis of ageing27
It is thus not surprising that Vit D deficiency could be a risk factor for AD. A 2019 meta-analysis
showed that Vit D deficiency (Vit D serum level <10 ng/mL) is positively correlated with the risk
of developing AD and every 10 ng/mL supplement of Vit D could reduce that risk by 17%, while
such an association was not found in Vit D insufficiency (Vit D serum level 10–20 ng/mL)28.
Vit D also helps the innate immune system by acting as an immunomodulator, exerting antiinflammatory effects, and playing a fundamental role in the maintenance of gut barrier integrity
and modulation of the gut microbiota. The interactions between Vit D and its receptor activate
specialized cells in the epithelium and lamina propria limiting the entrance of microbiota (and/or
their products) into the interstitium. The cells of the innate and adaptive immune systems would
clear the affected site in case lamina propria were invaded by bacteria. Once the site is cleared,
Vit D subdues the immune system restoring the homeostasis.
Vit D also influences the distribution of the faecal microbiota, increasing the levels of beneficial
bacterial species and lowering levels of pathogenic bacteria 29.
THE RATIONALE BEHIND TARGETING THE GUT MICROBIOTA
Only just recently, did the microbiome become of interest among neuroscientists. Recent works
evidencing the extensive communication between the gut and the brain have shown to have an
active role for gut bacteria in governing several aspects of CNS physiology30.
The gut microbiota (GM) is being studied more in depth in relation to its role in modulating
neuroinflammation in neurodegenerative diseases including AD. Therapeutic approaches
targeting gut dysbiosis are believed to be promising in altering disease pathogenesis through
different mechanisms31.
Although the multitude of factors and signals influencing microglial activity have not been fully
elucidated, its dysfunction has been implicated at the beginning and during the progression of
several neurodevelopmental and neurodegenerative diseases. To sustain brain homeostasis,
microglia continually survey their microenvironment through the dynamic extension and
retraction of their processes. Once a signal of infection or injury has been detected, microglia
11
change from a homeostatic state of surveillance to an activated one, facilitating antimicrobial or
tissue repair programs that restore homeostasis. Within the CNS, microglial activity is driven in
part by cytokines, chemokines, neurotransmitters and other molecules that regulate signalling
pathways that affect different brain functions.
Although previously believed to be shielded from the circulatory system by the blood–brain
barrier (BBB), microglial activity is now known to be affected by factors originating outside the
CNS, including the gut. Studies are now clarifying the role of gut microbiota in microglial
maturation, identity, and function, in steady state and disease conditions associated with
elevated microglial activation.
Together with preserving the integrity of the epithelial barrier along the gastrointestinal (GI)
tract, gut bacteria are decisive for the development/maturation of the host’s innate and adaptive
immune systems, nutrient absorption, metabolism, and protection against foreign invaders. The
gut microbiota functions work beyond the digestive tract in which they reside. The diverse
metabolites and signalling molecules produced by gut bacteria enter the systemic circulation,
facilitating the molecular communication between host and microbes in the entire body30 (Fig 5).
Fig. 5: The microbiota-gut-brain axis. The bidirectional communication between the brain and gut microbiota is
mediated by several pathways including the immune system, neuroendocrine system, enteric nervous system (ENS),
circulatory system, and vagus nerve. The routes of these pathways contain various neuroactive compounds including
microbial-derived metabolites, microbial-derived products, peptides, gut hormones, and neuroactive substances. Upon
entering the brain, metabolites can subsequently influence neurodevelopment and neurodegeneration of numerous
conditions, such as multiple sclerosis, Parkinson’s Disease, Alzheimer’s Disease, CNS malignancies, stroke, autism
spectrum disorder, depression, anxiety, stress, and schizophrenia32.
TO BE CONTINUED… SEE PART 2
12
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