ALZHEIMER’S DISEASE
Alzheimer's Disease (AD or Alz) is an age-related, non-reversible brain disorder that
develops over a period of years. Initially, people experience memory loss and
confusion, which may be mistaken for the kinds of memory changes that are
sometimes associated with normal aging. However, the symptoms of AD
gradually lead to behavior and personality changes, a decline in cognitive
abilities such as decision-making and language skills, and problems recognizing
family and friends. AD ultimately leads to a severe loss of mental function. These
losses are related to the worsening breakdown of the connections between
certain neurons in the brain and their eventual death. AD is one of a group of
disorders called dementias that are characterized by cognitive and behavioral
problems. It is the most common cause of dementia among people age 65 and
older.
There are three major hallmarks in the brain that are associated with the disease
processes of AD.
Amyloid plaques, which are made up of fragments of a protein called betaamyloid peptide mixed with a collection of additional proteins, remnants of
neurons, and bits and pieces of other nerve cells.
Neurofibrillary tangles (NFTs), found inside neurons, are abnormal collections of
a protein called tau. Normal tau is required for healthy neurons. However, in AD,
tau clumps together. As a result, neurons fail to function normally and eventually
die.
Loss of connections between neurons responsible for memory and learning.
Neurons can't survive when they lose their connections to other neurons. As
neurons die throughout the brain, the affected regions begin to atrophy, or shrink.
By the final stage of AD, damage is widespread and brain tissue has shrunk
significantly.
Scientists believe that for most people, Alzheimer's disease is caused by a
combination of genetic, lifestyle and environmental factors that affect the brain
over time.
The exact causes of Alzheimer's disease aren't fully understood, but at its
core are problems with brain proteins that fail to function normally, disrupt the
work of brain cells (neurons) and unleash a series of toxic events. Neurons are
damaged, lose connections to each other and eventually die.
The damage most often starts in the region of the brain that controls
memory, but the process begins years before the first symptoms. The loss of
neurons spreads in a somewhat predictable pattern to other regions of the brains.
By the late stage of the disease, the brain has shrunk significantly.
Researchers are focused on the role of two proteins:
Plaques. Beta-amyloid is a leftover fragment of a larger protein. When these
fragments cluster together, they appear to have a toxic effect on neurons and to
disrupt cell-to-cell communication. These clusters form larger deposits called
amyloid plaques, which also include other cellular debris.
Tangles. Tau proteins play a part in a neuron's internal support and transport
system to carry nutrients and other essential materials. In Alzheimer's disease, tau
proteins change shape and organize themselves into structures called
neurofibrillary tangles. The tangles disrupt the transport system and are toxic to
cells.
Understanding Alzheimer's and dementia
Alzheimer's is the most common cause of dementia, a general term for memory
loss and other cognitive abilities serious enough to interfere with daily life.
Alzheimer's disease accounts for 60 percent to 80 percent of dementia cases.
Alzheimer's is not a normal part of aging. The greatest known risk factor is
increasing age, and the majority of people with Alzheimer's are 65 and older. But
Alzheimer's is not just a disease of old age. Approximately 200,000 Americans
under the age of 65 have younger-onset Alzheimer’s disease (also known as earlyonset Alzheimer’s).
Alzheimer's worsens over time. Alzheimer's is a progressive disease, where
dementia symptoms gradually worsen over a number of years. In its early stages,
memory loss is mild, but with late-stage Alzheimer's, individuals lose the ability to
carry on a conversation and respond to their environment. Alzheimer's is the sixth
leading cause of death in the United States. On average, a person with
Alzheimer's lives four to eight years after diagnosis, but can live as long as 20 years,
depending on other factors.
Alzheimer's has no current cure, but treatments for symptoms are available and
research continues. Although current Alzheimer's treatments cannot stop
Alzheimer's from progressing, they can temporarily slow the worsening of
dementia symptoms and improve quality of life for those with Alzheimer's and their
caregivers. Today, there is a worldwide effort under way to find better ways to
treat the disease, delay its onset, and prevent it from developing.
Stages:
Mild Alzheimer's disease (early stage)
In the early stage of Alzheimer's, a person may function independently. He
or she may still drive, work and be part of social activities. Despite this, the person
may feel as if he or she is having memory lapses, such as forgetting familiar words
or the location of everyday objects.
Friends, family or others close to the individual begin to notice difficulties.
During a detailed medical interview, doctors may be able to detect problems in
memory or concentration.
Moderate Alzheimer's disease (middle stage)
Moderate Alzheimer's is typically the longest stage and can last for many years.
As the disease progresses, the person with Alzheimer's will require a greater level
of care.
During the moderate stage of Alzheimer’s, the dementia symptoms are more
pronounced. A person may have greater difficulty performing tasks, such as
paying bills, but they may still remember significant details about their life.
Severe Alzheimer's disease (late stage)
In the final stage of this disease, dementia symptoms are severe. Individuals
lose the ability to respond to their environment, to carry on a conversation and,
eventually, to control movement. They may still say words or phrases, but
communicating pain becomes difficult. As memory and cognitive skills continue
to worsen, significant personality changes may take place and individuals need
extensive help with daily activities.
The Origin of Alzheimer's Disease
When Alois Alzheimer met Auguste Deter in 1901, he could not have
suspected that her sad story would make his name a household word throughout
the world. Dr. Alzheimer was a young psychiatrist in his late 30s, a hard-working
clinician committed to understanding the relationship between brain disease and
mental illness. Following the death of his wife earlier that year, he had buried
himself in his clinical work, caring for psychiatric patients at the Community
Hospital for Mental and Epileptic Patients in Frankfurt, Germany. Auguste Deter
was only 50 years old when her husband noticed her increasing memory
problems. She soon became more fearful, paranoid, and aggressive, making it
necessary to admit her to the psychiatric hospital at age 51. She remained an
inpatient there until her death in 1906, although by then she was no longer under
Dr. Alzheimer’s care. He had since moved on to a research position at the Munich
Hospital under the leadership of Dr. Emil Kraepelin, one of the most influential
psychiatrists of his era.
Alzheimer’s former boss from Frankfurt, Dr. Emil Sioli, informed Dr. Alzheimer
of his former patient’s death. He sent her brain material to Alzheimer, who
examined Ms. Deter’s brain microscopically using new stains that revealed the
presence of what we now call amyloid plaques and neurofibrillary tangles.
Though it seems odd now, Alzheimer’s initial 1906 presentation linking this specific
brain pathology to a clinical syndrome was met with limited enthusiasm by his
peers.
The First Use of “Alzheimer’s Disease”
Alzheimer later published his descriptions of several similar patients in 1909
and Kraepelin included Ms. Deter’s case in the 1910 edition of his widely
respected psychiatry textbook. It was Kraepelin who named this dementia after
his junior colleague.
Auguste Deter was not an elderly woman at the onset of her illness, and
Alzheimer’s disease (AD) was therefore regarded as a “presenile dementia” to
distinguish it from the familiar “senile dementia” thought to result from agingrelated vascular disease. Further investigation, however, showed that plaques
and tangles were present in the brains of the majority of older adults with
symptoms of dementia.
In the late 1960’s, the British psychiatrists Tomlinson and Roth described the
importance of these plaques in older adults, and in 1970 Dr. Roth questioned the
meaningfulness of the age criterion that distinguished AD from “senile dementia
of the Alzheimer’s type.”
The Most Common Form of Dementia
The American neurologist, Robert Katzman, suggested in 1976 that we
should do away with the age distinction that separated pre-senile from senile
dementia of the Alzheimer’s type and by the early 1980’s AD was widely
recognized as the most common cause of dementia in older adults.
Causes of Alzheimer’s Disease
Scientists believe that many factors influence when Alzheimer's disease
begins and how it progresses.
Increasing age is the most important known risk factor for Alzheimer's. The
number of people with the disease doubles every 5 years beyond age 65. About
one-third of all people age 85 and older may have Alzheimer's disease.
The causes of late-onset Alzheimer's, the most common form of the disease,
probably include a combination of genetic, lifestyle, and environmental factors.
The importance of any one of these factors in increasing or decreasing the risk of
development Alzheimer's may differ from person to person.
Scientists are learning how age-related changes in the brain may harm
nerve cells and contribute to Alzheimer's damage. These age-related changes
include atrophy (shrinking) of certain parts of the brain, inflammation, production
of unstable molecules called free radicals, and breakdown of energy production
within cells.
As scientists learn more about this devastating disease, they realize that
genes also play an important role.
Genetics 101
Each human cell contains the instructions a cell needs to do its job. These
instructions are made up of DNA, which is packed tightly into structures called
chromosomes. Each chromosome has thousands of segments called genes.
Genes are passed down from a person's birth parents. They carry
information that defines traits such as eye color and height. Genes also play a
role in keeping the body's cells healthy. Problems with genes—even small
changes to a gene—can cause diseases like Alzheimer's disease.
The Genetics of Disease
Some diseases are caused by a genetic mutation, or permanent change
in one or more specific genes. If a person inherits from a parent a genetic
mutation that causes a certain disease, then he or she will usually get the disease.
Sickle cell anemia, cystic fibrosis, and early-onset familial Alzheimer's disease are
examples of inherited genetic disorders.
In other diseases, a genetic variant may occur. A single gene can have
many variants. Sometimes, this difference in a gene can cause a disease directly.
More often, a variant plays a role in increasing or decreasing a person's risk of
developing a disease or condition. When a genetic variant increases disease risk
but does not directly cause a disease, it is called a genetic risk factor.
Alzheimer's Disease Genetics
There are two types of Alzheimer's—early-onset and late-onset. Both types
have a genetic component.
Late-Onset Alzheimer's
Signs first appear in a person's mid-60s
Most common type
May involve a gene called APOE ɛ4
Early-Onset Alzheimer's
Signs first appear between a person's
30s and mid-60s
Very rare
Usually caused by gene changes
passed down from parent to child
Late-Onset Alzheimer's Disease
Most people with Alzheimer's have the late-onset form of the disease, in
which symptoms become apparent in the mid-60s.
Researchers have not found a specific gene that directly causes the lateonset form of the disease. However, one genetic risk factor—having one form of
the apolipoprotein E (APOE) gene on chromosome 19—does increase a person's
risk. APOE comes in several different forms, or alleles:
APOE ɛ2 is relatively rare and may provide some protection against the
disease. If Alzheimer's disease occurs in a person with this allele, it usually develops
later in life than it would in someone with the APOE ɛ4 gene.
APOE ɛ3, the most common allele, is believed to play a neutral role in the
disease—neither decreasing nor increasing risk.
APOE ɛ4 increases risk for Alzheimer's disease and is also associated with
an earlier age of disease onset. A person has zero, one, or two APOE ɛ4 alleles.
Having more APOE ɛ4 alleles increases the risk of developing Alzheimer's.
APOE ɛ4 is called a risk-factor gene because it increases a person's risk of
developing the disease. However, inheriting an APOE ɛ4 allele does not mean
that a person will definitely develop Alzheimer's. Some people with an APOE ɛ4
allele never get the disease, and others who develop Alzheimer's do not have
any APOE ɛ4 alleles.
Early-Onset Alzheimer's Disease
Early-onset Alzheimer's disease occurs between a person's 30s to mid-60s
and represents less than 10 percent of all people with Alzheimer's. Some cases are
caused by an inherited change in one of three genes, resulting in a type known
as early-onset familial Alzheimer's disease, or FAD. For other cases of early-onset
Alzheimer's, research suggests there may be a genetic component related to
factors other than these three genes.
A child whose biological mother or father carries a genetic mutation for
early-onset FAD has a 50/50 chance of inheriting that mutation. If the mutation is
in fact inherited, the child has a very strong probability of developing early-onset
FAD.
Early-onset FAD is caused by any one of a number of different single gene
mutations on chromosomes 21, 14, and 1. Each of these mutations causes
abnormal proteins to be formed. Mutations on chromosome 21 cause the
formation of abnormal amyloid precursor protein (APP). A mutation on
chromosome 14 causes abnormal presenilin 1 to be made, and a mutation on
chromosome 1 leads to abnormal presenilin 2.
Each of these mutations plays a role in the breakdown of APP, a protein
whose precise function is not yet fully understood. This breakdown is part of a
process that generates harmful forms of amyloid plaques, a hallmark of
Alzheimer's disease.
Health, Environmental, and Lifestyle Factors
Research suggests that a host of factors beyond genetics may play a role
in the development and course of Alzheimer's disease. There is a great deal of
interest, for example, in the relationship between cognitive decline and vascular
conditions such as heart disease, stroke, and high blood pressure, as well as
metabolic conditions such as diabetes and obesity. Ongoing research will help us
understand whether and how reducing risk factors for these conditions may also
reduce the risk of Alzheimer's.
A nutritious diet, physical activity, social engagement, and mentally
stimulating pursuits have all been associated with helping people stay healthy as
they age. These factors might also help reduce the risk of cognitive decline and
Alzheimer's disease. Clinical trials are testing some of these possibilities.
What Happens to the Brain in Alzheimer's Disease?
The healthy human brain contains tens of billions of neurons—specialized
cells that process and transmit information via electrical and chemical signals.
They send messages between different parts of the brain, and from the brain to
the muscles and organs of the body. Alzheimer’s disease disrupts this
communication among neurons, resulting in loss of function and cell death.
Key Biological Processes in the Brain
Most neurons have three basic parts: a cell body, multiple dendrites, and an axon.
The cell body contains the nucleus, which houses the genetic blueprint that
directs and regulates the cell’s activities.
Dendrites are branch-like structures that extend from the cell body and collect
information from other neurons.
The axon is a cable-like structure at the end of the cell body opposite the
dendrites and transmits messages to other neurons.
The function and survival of neurons depend on several key biological processes:
Communication. Neurons are constantly in touch with neighboring brain cells.
When a neuron receives signals from other neurons, it generates an electrical
charge that travels down the length of its axon and releases neurotransmitter
chemicals across a tiny gap, called a synapse. Like a key fitting into a lock, each
neurotransmitter molecule then binds to specific receptor sites on a dendrite of a
nearby neuron. This process triggers chemical or electrical signals that either
stimulate or inhibit activity in the neuron receiving the signal. Communication
often occurs across networks of brain cells. In fact, scientists estimate that in the
brain’s communications network, one neuron may have as many as 7,000
synaptic connections with other neurons.
Metabolism. Metabolism—the breaking down of chemicals and nutrients within
a cell—is critical to healthy cell function and survival. To perform this function, cells
require energy in the form of oxygen and glucose, which are supplied by blood
circulating through the brain. The brain has one of the richest blood supplies of
any organ and consumes up to 20 percent of the energy used by the human
body—more than any other organ.
Repair, remodeling, and regeneration. Unlike many cells in the body, which are
relatively short-lived, neurons have evolved to live a long time—more than 100
years in humans. As a result, neurons must constantly maintain and repair
themselves. Neurons also continuously adjust, or “remodel,” their synaptic
connections depending on how much stimulation they receive from other
neurons. For example, they may strengthen or weaken synaptic connections, or
even break down connections with one group of neurons and build new
connections with a different group. Adult brains may even generate new
neurons—a process called neurogenesis. Remodeling of synaptic connections
and neurogenesis are important for learning, memory, and possibly brain repair.
Neurons are a major player in the central nervous system, but other cell
types are also key to healthy brain function. In fact, glial cells are by far the most
numerous cells in the brain, outnumbering neurons by about 10 to 1. These cells,
which come in various forms—such as microglia, astrocytes, and
oligodendrocytes—surround and support the function and healthy of neurons. For
example, microglia protect neurons from physical and chemical damage and
are responsible for clearing foreign substances and cellular debris from the brain.
To carry out these functions, glial cells often collaborate with blood vessels in the
brain. Together, glial and blood vessel cells regulate the delicate balance within
the brain to ensure that it functions at its best.
How Does Alzheimer’s Disease Affect the Brain?
The brain typically shrinks to some degree in healthy aging but, surprisingly,
does not lose neurons in large numbers. In Alzheimer’s disease, however, damage
is widespread, as many neurons stop functioning, lose connections with other
neurons, and die. Alzheimer’s disrupts processes vital to neurons and their
networks, including communication, metabolism, and repair.
At first, Alzheimer’s disease typically destroys neurons and their connections
in parts of the brain involved in memory, including the entorhinal cortex and
hippocampus. It later affects areas in the cerebral cortex responsible for
language, reasoning, and social behavior. Eventually, many other areas of the
brain are damaged. Over time, a person with Alzheimer’s gradually loses his or
her ability to live and function independently. Ultimately, the disease is fatal.
What Are the Main Characteristics of the Brain with Alzheimer’s?
Many molecular and cellular changes take place in the brain of a person
with Alzheimer’s disease. These changes can be observed in brain tissue under
the microscope after death. Investigations are underway to determine which
changes may cause Alzheimer’s and which may be a result of the disease.
Amyloid Plaques
The beta-amyloid protein involved in Alzheimer’s comes in several different
molecular forms that collect between neurons. It is formed from the breakdown
of a larger protein, called amyloid precursor protein. One form, beta-amyloid 42,
is thought to be especially toxic. In the Alzheimer’s brain, abnormal levels of this
naturally occurring protein clump together to form plaques that collect between
neurons and disrupt cell function. Research is ongoing to better understand how,
and at what stage of the disease, the various forms of beta-amyloid influence
Alzheimer’s.
Neurofibrillary Tangles
Neurofibrillary tangles are abnormal accumulations of a protein called tau
that collect inside neurons. Healthy neurons, in part, are supported internally by
structures called microtubules, which help guide nutrients and molecules from the
cell body to the axon and dendrites. In healthy neurons, tau normally binds to and
stabilizes microtubules. In Alzheimer’s disease, however, abnormal chemical
changes cause tau to detach from microtubules and stick to other tau molecules,
forming threads that eventually join to form tangles inside neurons. These tangles
block the neuron’s transport system, which harms the synaptic communication
between neurons.
Emerging evidence suggests that Alzheimer’s-related brain changes may
result from a complex interplay among abnormal tau and beta-amyloid proteins
and several other factors. It appears that abnormal tau accumulates in specific
brain regions involved in memory. Beta-amyloid clumps into plaques between
neurons. As the level of beta-amyloid reaches a tipping point, there is a rapid
spread of tau throughout the brain.
Chronic Inflammation
Research suggests that chronic inflammation may be caused by the
buildup of glial cells normally meant to help keep the brain free of debris. One
type of glial cell, microglia, engulfs and destroys waste and toxins in a healthy
brain. In Alzheimer’s, microglia fail to clear away waste, debris, and protein
collections, including beta-amyloid plaques. Researchers are trying to find out
why microglia fail to perform this vital function in Alzheimer’s.
One focus of study is a gene called TREM2. Normally, TREM2 tells the
microglia cells to clear beta-amyloid plaques from the brain and helps fight
inflammation in the brain. In the brains of people where this gene does not
function normally, plaques build up between neurons. Astrocytes—another type
of glial cell—are signaled to help clear the buildup of plaques and other cellular
debris left behind. These microglia and astrocytes collect around the neurons but
fail to perform their debris-clearing function. In addition, they release chemicals
that cause chronic inflammation and further damage the neurons they are
meant to protect.
Vascular Contributions to Alzheimer’s Disease
People with dementia seldom have only Alzheimer’s-related changes in
their brains. Any number of vascular issues—problems that affect blood vessels,
such as beta-amyloid deposits in brain arteries, atherosclerosis (hardening of the
arteries), and mini-strokes—may also be at play.
Vascular problems may lead to reduced blood flow and oxygen to the
brain, as well as a breakdown of the blood-brain barrier, which usually protects
the brain from harmful agents while allowing in glucose and other necessary
factors. In a person with Alzheimer’s, a faulty blood-brain barrier prevents glucose
from reaching the brain and prevents the clearing away of toxic beta-amyloid
and tau proteins. This results in inflammation, which adds to vascular problems in
the brain. Because it appears that Alzheimer’s is both a cause and consequence
of vascular problems in the brain, researchers are seeking interventions to disrupt
this complicated and destructive cycle.
Loss of Neuronal Connections and Cell Death
In Alzheimer’s disease, as neurons are injured and die throughout the brain,
connections between networks of neurons may break down, and many brain
regions begin to shrink. By the final stages of Alzheimer’s, this process—called brain
atrophy—is widespread, causing significant loss of brain volume.
Incidence of Alzheimer’s Disease
The global prevalence of dementia has been estimated to be as high as
24 million, and is predicted to double every 20 years until at least 2040. As the
population worldwide continues to age, the number of individuals at risk will also
increase, particularly among the very old. Alzheimer disease is the leading cause
of dementia beginning with impaired memory. The neuropathological hallmarks
of Alzheimer disease include diffuse and neuritic extracellular amyloid plaques in
brain that are frequently surrounded by dystrophic neurites and intraneuronal
neurofibrillary tangles. The etiology of Alzheimer disease remains unclear, but it is
likely to be the result of both genetic and environmental factors. In this review we
discuss the prevalence and incidence rates, the established environmental risk
factors, and the protective factors, and briefly review genetic variants
predisposing to disease.
Alzheimer disease is characterized by progressive cognitive decline usually
beginning with impairment in the ability to form recent memories, but inevitably
affecting all intellectual functions and leading to complete dependence for
basic functions of daily life, and premature death. The pathological
manifestations of Alzheimer disease include diffuse and neuritic extracellular
amyloid plaques and intracellular neurofibrillary tangles accompanied by
reactive microgliosis, dystrophic neurites, and loss of neurons and synapses (see
Serrano-Pozo et al. 2011). While these pathological lesions do not fully explain the
clinical features of the disease, it has been hypothesized that alterations in the
production and processing of amyloid β-protein may be the principal initiating
factor. The underlying causes of these multifaceted changes remain unknown,
but advancing age, and genetic and nongenetic antecedent factors are
thought to play important roles. Alzheimer disease is the most frequent cause of
dementia in Western societies. In the US, approximately 5.5 million people are
affected, and the prevalence worldwide is estimated to be as high as 24 million.
Given that both established and developing nations are rapidly aging, the
frequency is expected to double every 20 years until 2040. The magnitude of the
impending rise owing to societal aging is considerable and will be a costly public
health burden in the years to come.
DEFINITIONS AND CRITERIA
In 1984, representatives from the National Institute of Neurological and
Communicative Disorders and Stroke and the Alzheimer Disease and Related
Disorders Association (NINCDS-ADRDA) developed a uniform set of criteria to
enable clinicians and researchers to maintain consistency in the diagnosis. They
included aspects of medical history, clinical examination, neuropsychological
testing, and laboratory assessments (McKhann et al. 1984). These criteria have
been remarkably reliable and valid for the diagnosis of AD over the past three
decades (Galasko et al. 1994; Lim et al. 1999). The criteria were developed with
the intent of accurately associating the clinical symptoms with the
neuropathological manifestations after death. Levels of certainty were
established that were labeled as definite for autopsy-confirmed disease,
probable for the typical clinical syndrome without intervening issues and possible
for diagnoses complicated by disorders that might contribute to the dementia.
The criteria facilitated estimates of the prevalence and incidence rates of
clinically diagnosed probable and possible AD.
The NINCDS-ADRDA criteria have very recently been updated (McKhann
et al. 2011). With major advances in neuropsychological assessment, brain
imaging and the neuropathological, biochemical and genetic understanding of
this disease, revisions were considered a necessity. The breadth of the AD
phenotype in society is greater than was previously thought. For example,
neuropathological changes may precede clinical dementia by a decade or
more. The growing use of brain imaging and cerebrospinal fluid biomarkers (see
below) may yield both higher specificity and sensitivity in the diagnosis and thus
are considered in the updated diagnostic criteria, especially when used for
clinical research. It has become increasingly clear that cerebrovascular disease
can coexist with AD to a greatly varying extent, further contributing to the
cognitive and physical dysfunction.
A set of newly proposed criteria are similar to, but distinct from, those in the
1984 NINCDS-ADRDA criteria, with updates that include the recognition of both
amnestic and nonamnestic symptom onset and alterations in numerous other
cognitive domains. Further, cerebrovascular disease is now recognized as a
contributor to dementia, defined by a history of a stroke temporally related to the
onset or worsening of cognitive impairment, the presence of multiple or extensive
infarcts, or severe burden of hyperintense white matter lesions by MRI.
Accordingly, the presence of substantial cerebrovascular pathology reduces the
certainty of a clinical diagnosis of AD to possible. Hallucinations, delusions,
Parkinson-like motor manifestations and realted findings can suggest dementia
with Lewy bodies or other forms of dementia
FREQUENCY OF ALZHEIMER DISEASE
In 2005, Alzheimer Disease International commissioned an international
group of experts to reach a consensus on dementia prevalence and estimated
incidence in 14 World Health Organization regions, based on epidemiological
data acquired over recent years. The results suggested that 24.2 million people
lived with dementia at that time, with 4.6 million new cases arising every year (Ferri
et al. 2005). North America and Western Europe have at age 60 the highest
prevalence of dementia (6.4 and 5.4% of the population at age 60), followed by
Latin America (4.9%) and China and its developing western-Pacific neighbors
(4.0%). The annual incidence rates (per 1000) for these countries were estimated
at 10.5 for North America, 8.8 for Western Europe, 9.2 for Latin America and 8.0 for
China and its developing western-Pacific neighbors, increasing exponentially with
age in all countries, especially through the seventh and eighth decades of life.
The prevalence rates for AD also rise exponentially with age, increasing
markedly after 65 years. There is almost a 15-fold increase in the prevalence of
dementia, predominately Alzheimer disease, between the ages of 60 and 85
years (Evans et al. 1989). Compared with Africa, Asia and Europe, the prevalence
of AD appears to be much higher in the US, which may relate to methods of
ascertainment. The prevalence may be higher among African-American and
Hispanic populations living in the US, but lower for Africans in their homelands, for
reasons that remain uncertain (Ogunniyi et al. 2000; Hendrie et al. 2001).
In 1998, Brookmeyer et al. estimated the age-specific incidence rates of AD
based on studies in Boston, Framingham, Rochester, and Baltimore. These rates
doubled every 5 years after the age of 60 and rose from about 0.17% per year at
age 65 to 0.71, 1.0, and 2.92% per year, respectively, at 75, 80, and 85 (Brookmeyer
et al. 1998). This observation is consistent with the vast majority of studies that have
estimated the age-specific incidence of AD by sex and by ethnic group (Fig. 1;
Bachman et al. 1993; Letenneur et al. 1994; Brayne et al. 1995; Hebert et al. 1995;
Aevarsson and Skoog 1996; Fratiglioni et al. 1997; Andersen et al. 1999; Copeland
et al. 1999; Launer et al. 1999; Ganguli et al. 2000; Kawas et al. 2000; Lobo et al.
2000; Chandra et al. 2001; Hendrie et al. 2001; Tang et al. 2001; Di Carlo et al. 2002;
Edland et al. 2002; Knopman et al. 2002; Kukull et al. 2002; Fitzpatrick et al. 2004;
Lopez-Pousa et al. 2004; Nitrini et al. 2004; Ravaglia et al. 2005a; Jellinger and
Attems 2010).
Two factors contribute to the difficulty in establishing accurate incidence
rates of AD: (1) determining the age at onset; and (2) defining a disease-free
population. Nonetheless, studies illustrate the consistent increase in incidence
rates with age from approximately 0.5% per year among individuals aged 65–70
to approximately 6–8% for individuals over age 85. The rapid rise in the frequency
of AD with advancing age, combined with the relatively long duration of the
illness, accounts in large part for the high prevalence of the disease worldwide.
Improvement and standardization of diagnostic methods have provided a
means to compare estimates of the frequency of AD across various populations.
ANTECEDENT RISK FACTORS THAT INCREASE THE RISK OF ALZHEIMER DISEASE
A large number of factors has been associated with increased risk of AD,
but among those, cerebrovascular disease and it antecedents are the most
consistently reported (Table 1). A history of diabetes, hypertension, smoking,
obesity, and dyslipidemia have all been found to increase risk. Interestingly
cerebrovascular disease, including large cortical infarcts, single strategically
placed infarcts, multiple small infarcts, cerebral hemorrhage, cortical changes
owing to hypoperfusion, white matter changes and vasculopathies, are all
antecedents to dementia in general (Barba et al. 2000; de Koning et al. 2000;
Desmond et al. 2000, 2002; Zhu et al. 2000; Henon et al. 2001; Klimkowicz et al.
2002; Honig et al. 2003; Liebetrau et al. 2003; Ivan et al. 2004; Linden et al. 2004;
Srikanth et al. 2004; Tang et al. 2004; Zhou et al. 2004; de Koning et al. 2005; Kuller
et al. 2005; Gamaldo et al. 2006; Jin et al. 2006; Simons et al. 2006; Srikanth et al.
2006; Yip et al. 2006; Jin et al. 2008; Reitz et al. 2008; Rastas et al. 2010).
TABLE 1:
Factors that modify the
risk of Alzheimer disease
Antecedent
Direction
Cardiovascular disease
Increased
Smoking
Increased
Possible mechanisms
Parenchymal destruction
Strategic location
↑ Aβ deposition
Cerebrovascular effects
Oxidative stress
Hypertension
Type II diabetes
Increased
decreased
Increased
Obesity
Increased
Traumatic head injury
Increased
Education
Decreased
Leisure activity
Decreased
Mediterranean diet
Decreased
Physical activity
Decreased
and Microvascular disease
Cerebrovascular effect
Insulin and Aβ compete
for clearance
Increased risk of type II
diabetes inflammatory
↑Aβ
and
amyloid
precursor
protein
deposition
Provides
cognitive
reserve
Improves
lipid
metabolism,
mental
stimulation
Antioxidant,
antiinflammatory
Activates brain plasticity,
promotes
brain
vascularization
Cerebrovascular Disease
While it is clear that cerebrovascular disease may present with
manifestations resembling dementia, purely vascular dementia is uncommon.
More often cerebrovascular disease co-exists with AD, so that evidence of both
vascular disease and prototypical AD manifestations is present (Schneider and
Bennett 2010). Pendlebury and Rothwell (2009) analyzed data from several
hospital- and population-based cohorts (7511 patients) and estimated a
frequency of new-onset dementia to be approximately 7% following a first stroke.
Interestingly, the twofold increased risk of dementia after incident stroke was
independent of the level or the rate of change of prestroke cognitive function,
suggesting that prestroke cognitive function is not a major determinant of the
effect of stroke on the risk of poststroke dementia (Reitz et al. 2008). The proposed
mechanisms by which stroke could lead to cognitive impairment include
destruction of brain parenchyma with atrophy (Fein et al. 2000; Jellinger 2002),
damage in strategic locations that leads to amnestic syndromes, such as
thalamic strokes, an increase in Aβ deposition and the combination of vascular
and Alzheimer-type pathology (Blennow et al. 2006). As one possible mechanism
for an increase in Aβ, there is evidence from rodent models of ischemia and
hypoxia owing to hypoperfusion that a resulting overexpression of p25 and cdk5
increases levels of BACE1, which in turn increases amyloid precursor protein (APP)
processing (Wen et al. 2007, 2008).
White matter hyperintensities are frequently observed by MRI in patients
with dementia, but the mechanisms by which white matter changes contribute
to cognitive decline are unclear. Moreover because hypertension, diabetes and
microvasuclar disease are each associated with these changes, there is no clear
process to explain the effect on cognition or their role in Alzheimer disease.
Thalamic vascular disease can lead to lower performance on cognitive tasks,
particularly those associated with frontal and temporal lobe function, including
memory storage and retrieval (Swartz et al. 2008; Wright et al. 2008).
Hypertension
Cross-sectional and longitudinal studies implicate blood pressure as a
possible contributor to late-life dementia. Observational studies of the association
between elevated blood pressure during middle age and late-life cognitive
impairment suggest that mid-life hypertension increases the risk of late-life
dementia (Kilander et al. 2000; Launer et al. 2000; Wu et al. 2003; Yamada et al.
2003; Elias et al. 2004; Whitmer et al. 2005b). When hypertension is assessed in later
life, the association is somewhat ambiguous, in that both high and abnormally
low blood pressure are associated with dementia (Skoog et al. 1996; Knopman et
al. 2001; Morris et al. 2001; Ruitenberg et al. 2001; Tyas et al. 2001; Bohannon et al.
2002; Lindsay et al. 2002; Posner et al. 2002; Elias et al. 2003; Kuller et al. 2003; Piguet
et al. 2003; Qiu et al. 2003; Reinprecht et al. 2003; Verghese et al. 2003a; Hebert
et al. 2004; Solfrizzi et al. 2004; Tervo et al. 2004; Borenstein et al. 2005; Petitti et al.
2005; Waldstein et al. 2005). With Alzheimer disease onset and progression, blood
pressure begins to decrease, possibly related to vessel stiffening, weight loss, and
changes in the autonomic regulation of blood flow. Hypertension is a treatable
medical disorder, but clinical trials of antihypertensive medications in AD patients
have been attempted with inconsistent results (Forette et al. 2002; Lithell et al.
2003; Tzourio et al. 2003; Peters et al. 2010).
Type II Diabetes
The presence of type II diabetes is associated with a approximately twofold
increased risk of AD (risk ratios vary between 1.5 and 4.0; Luchsinger et al. 2001;
Peila et al. 2002; Farris et al. 2003; Luchsinger et al. 2004a). It has been suggested
that diabetes directly affects Aβ accumulation in the brain because
hyperinsulinemia, which accompanies type II diabetes, disrupts brain Aβ
clearance by competing for the insulin-degrading enzyme (Selkoe 2000; Farris et
al. 2003). Receptors for advanced glycation end-products, which also play a role
in the pathogenesis of diabetes, are present in cels associated with senile plaques
and neurofibrillary tangles have been shown to be one example of a cell surface
receptor for Aβ. Excess adipose tissue may also predispose to type II diabetes by
producing adipokines critical to metabolism and cytokines important in
inflammation. Adiponectin, leptin, resistin, TNF-α and IL-6 are also produced and
correlate with insulin resistance and hyperinsulinemia, which in turn may directly
or indirectly affect AD risk (Trujillo and Scherer 2005; Yu and Ginsberg 2005). A
meta-analysis of longitudinal studies examining type II diabetes and other
disorders of glucose or insulin levels found a pooled effect size for diabetes of 1.54
in increasing AD risk (95% confidence interval, CI, 1.33–1.79; z = 5.7; p < .001;
Profenno et al. 2009).
Reger et al. (2008) showed that the administration of intranasal insulin
improved cognitive performance in the early phases of AD and in patients with
amnestic mild cognitive impairment, as did a 6-month trial of the PPAR-γ agonist,
rosiglitazone (Watson et al. 2005). Another study (Risner et al. 2006) in patients with
AD lacking the APOE-ε4 allele showed significant although small improvements in
cognitive and functional improvement in response to rosiglitazone, whereas in a
study by Sato et al. (2009), treatment with 15–30 mg pioglitazone daily for 6
months led to improvements in cognitive function and regional cerebral blood
flow in the parietal lobe.
Body Weight
Several cross-sectional and case–control studies found that low body mass
index or being underweight were apparent risk factors for dementia and agerelated brain changes such as atrophy (Faxen-Irving et al. 2005). In contrast
several prospective studies linked both low and high body weight, weight loss and
weight gain to risk of AD (Nourhashemi et al. 2002, 2003; Gustafson et al. 2003;
Bagger et al. 2004; Brubacher et al. 2004; Buchman et al. 2005; Goble 2005; Jeong
et al. 2005; Kivipelto et al. 2005; Razay and Vreugdenhil 2005; Rosengren et al.
2005; Stewart et al. 2005; Tabet 2005; Whitmer et al. 2005a; Waldstein and Katzel
2006; Arbus et al. 2008; Atti et al. 2008). The strongest effect was in a meta-analysis
associating obesity (assessed by high body mass index) and the risk of AD (odds
ratio, OR, 1.59 95% CI 1.02–2.5; z = 2.0; p = .042) (Profenno et al. 2009). The
mechanisms by which body weight alters disease risk are unknown, but may
include effects such as insulin resistance or the co-incidence of type II diabetes.
Smoking
Case–control studies initially suggested that smoking lowers the risk of
Alzheimer disease, but subsequent prospective studies showed an increased risk
or no association (Doll et al. 2000). Smoking may increase the risk of dementia by
augmentation of cholinergic metabolism, that is, up-regulating cholinergic
nicotinic receptors in the brain (Whitehouse et al. 1988). Cholinergic deficits,
characterized by reduced levels of acetylcholine, choline acetyl transferase
and/or nicotinic acetyl choline receptors, are invariably found in AD brains.
However, nicotine itself increases acetylcholine release, elevates the number of
nicotinic receptors, and improves attention and information processing. These
actions may be opposed by elevated oxidative stress caused by smoking, and
oxidative stress has been implicated as a putative AD mechanism (Rottkamp et
al. 2000; Perry et al. 2002) through the generation of free radicals and affecting
inflammatory–immune systems, which in turn can activate phagocytes that
generate further oxidative damage (Traber et al. 2000).
Traumatic Brain Injury
Compared with those without a history of trauma, individuals having
suffered traumatic brain injury have a higher risk of dementia, particularly those
who carry the APOE-ε4 allele (Koponen et al. 2004). A meta-analyses
demonstrated that the risk of dementia is higher among men (but not women)
with a history of traumatic brain injury (Fleminger et al. 2003). Postmortem and
experimental studies do support a link: After human brain injury, both Aβ
deposition (Hartman et al. 2002; Iwata et al. 2002; Stone et al. 2002) and
intraneuronal tau pathology are increased, even in younger patients (Smith et al.
2003). In addition, CSF Aβ levels are elevated and APP is overproduced
(Emmerling et al. 2000; Franz et al. 2003).
PROTECTIVE FACTORS THAT REDUCE RISK OF ALZHEIMER DISEASE
Cognitive Reserve
Individuals with intellectually enriched lifestyles, such as those with high
educational and/or occupational attainment, have a reduced risk of expressing
AD pathology clinically. While several studies reported no association between
educational level and risk of AD (Hall et al. 2000; Chandra et al. 2001), a lower risk
of dementia in general in subjects with higher education has been reported by
several others worldwide (Evans et al. 1993, 1997; Letenneur et al. 1994, 1999; Stern
et al. 1994; White et al. 1994; Qiu et al. 2001).
There is also evidence for a role of education in age-related cognitive
decline, with several studies of “normal aging” reporting slower cognitive and
functional decline in individuals with higher educational attainment (Chodosh et
al. 2002). These studies suggest that the same education-related factors that
delay the onset of AD-type dementia also allow individuals to cope more
effectively with brain changes encountered in normal aging. In an ethnically
diverse cohort of nondemented elders in New York City, increased literacy was
also associated with slower decline in memory, executive function, and language
skills (Manly et al. 2005).
Numerous studies have also explored the relationship between leisure
activities and incident dementia. Community activities and gardening were also
protective for incident dementia in China (Zhang et al. 1999). Having an extensive
social network was protective for the development of dementia (Fratiglioni et al.
2004), and engagement in mental, social, and other productive activities was
associated with decreased risk of incident dementia (Wang et al. 2002).
Participation in a variety of leisure activities characterized as intellectual (e.g.,
reading, playing games, going to classes) or social engagements (e.g., visiting
friends or relatives) was assessed in another population study of nondemented
elderly in New York (Scarmeas et al. 2001). During follow-up, subjects with high
leisure activity had 38% less risk of developing dementia. In another prospective
study, frequency of participation in common cognitive activities (i.e., reading a
newspaper, magazine, or book) was assessed at baseline for 801 elderly Catholic
nuns, priests and brothers without dementia (Wilson et al. 2002a). Finally, in
another prospective cohort from New York, participation in leisure activities,
particularly reading, playing board games or musical instruments, and dancing,
was associated with a reduced risk of incident dementia (Verghese et al. 2003b).
Increased participation in cognitive activities was also associated with reduced
rates of memory decline in this study.
A meta-analysis examined cohort studies of the effects of education,
occupation, premorbid IQ and mental activities on dementia risk (Valenzuela
and Sachdev 2005). A summary analysis was based on an integrated total of
29,279 individuals from 22 studies. The median follow-up was 7.1 years. The
summary odds ratio for incident dementia for individuals with high brain reserve
compared with low brain reserve was 0.54 (95% CI 0.49–0.59, p < 0.0001), that is, a
decreased risk of 46%. Eight out of 33 data sets showed no significant effect,
whereas 25 out of 33 demonstrated a significant protective effect. The authors
found a significant negative association between incident dementia risk (based
on differential education) and the overall dementia rate for each cohort (r =
−0.57, p = 0.04), indicating that in negative studies there was a lower overall risk
of incident dementia in the cohort.
In contrast to the studies above, in which greater cognitive reserve was
associated with better outcomes, a series of studies of patients with AD suggested
that those with higher reserve have poorer outcomes (Table 1). In prospective
studies of AD subjects matched for clinical severity at baseline (Geerlings et al.
1999; Stern et al. 1999), patients with greater education or occupational
attainment died sooner than those with less attainment. Similarly, higher
educational or occupational attainment (Stern et al. 1999; Scarmeas et al.
2006a), increased engagement in leisure activities (Helzner et al. 2007), and
greater lifetime cognitive activity (Wilson et al. 2010) have each been associated
with more rapid cognitive decline in patients with diagnosed AD. Although at first
these findings appear contra-intuitive, they are consistent with the cognitive
reserve hypothesis. The hypothesis predicts that, at any level of assessed clinical
severity, the underlying pathology of Alzheimer disease is more advanced in
patients with higher than those with less cognitive reserve. This would result in the
clinical disease emerging when pathology was more advanced, as suggested by
the incidence studies reviewed above. This disparity in degree of pathology
would be present at more advanced clinical stages of the disease as well. At
some point the greater degree of pathology in the high-reserve patients would
result in more rapid death. Higher educational attainment and greater
engagement in leisure activities and lifetime cognitive activities have also been
associated with more rapid cognitive decline in patients with Alzheimer disease.
Diet
Dietary fats can increase cholesterol levels, which in turn can increase
vascular risk in the brain. This sequence may also increase the risk of AD (Sparks et
al. 2000). Intake of saturated fats in the fifth (highest) quintile compared with the
first quintile of dietary fats was associated with a doubling of risk of incident
Alzheimer disease. Trans-unsaturated fats were associated with a 3-times-higher
risk of developing AD, whereas the highest intake of n-6 polyunsaturated fats and
monounsaturated fat reduced AD risk (Morris et al. 2003). An increased risk of AD
has also been associated with higher intake of total and saturated fat, with no
evidence of an association with polyunsaturated fat (Luchsinger et al. 2002).
Omega-3 fatty acids stems are essential dietary components in early brain
development. Many studies have found that consumption of fish or omega-3 fatty
acids is associated with a reduced risk of AD (Morris et al. 2003; Schaefer et al.
2006; van Gelder et al. 2007). For example, a study in France found that weekly
consumption of fish was associated with reduced AD risk, and regular
consumption of omega-3 rich oils was associated with increased risk of all causes
of dementia (Barberger-Gateau et al. 2007).
Two studies found a lower risk of Alzheimer disease in individuals with a
higher dietary intake of vitamin D (Engelhart et al. 2002; Morris et al. 2002). This
association was not noted in a third study, perhaps because the level of vitamin
D intake was lower (Luchsinger et al. 2003).
Total homocysteine has also been inconsistently associated with AD
(Luchsinger et al. 2004b; Seshadri 2006; Reitz et al. 2009). Concentrations of
homocysteine are largely determined by certain B vitamins. Based on folate levels
measured in serum, there was preliminary evidence from two studies that low
folate levels are associated with increased AD risk (Wang et al. 2001; Ravaglia et
al. 2005b). Some studies that used estimated dietary intake of folate and B
vitamins based on self-reported information reported conflicting results. One
reported an association between higher intake of folate and reduced risk of AD
(Luchsinger et al. 2007), whereas another did not find a significant reduction in AD
risk associated with folate intake (Morris et al. 2006). Neither study found an
association between vitamins B6 or B12 and risk of AD.
Inconsistencies in the existing literature regarding some of the above
dietary elements and AD risk may be a result of failure to consider possible
additive and interactive (antagonistic or synergistic) effects among nutritional
components, which may be better captured in a composite dietary pattern such
as the Mediterranean diet. The latter is characterized by high intake of
vegetables, legumes, fruits, and cereals; high intake of unsaturated fatty acids
(mostly in the form of olive oil), but low intake of saturated fatty acids; a
moderately high intake of fish; a low-to-moderate intake of dairy products (mostly
cheese or yogurt); a low intake of meat and poultry; and regular but moderate
amounts of ethanol, primarily in the form of wine and generally during meals
(Trichopoulou et al. 2003). In one study (Scarmeas et al. 2006b), higher adherence
to the Mediterranean diet was associated with lower risk of AD (hazard ratio, 0.91;
95% CI, 0.83–0.98; p = 0.015). Compared with subjects in the lowest Mediterranean
diet tertile, subjects in the middle tertile had an AD hazard ratio of 0.85 (95% CI,
0.63–1.16) and those in the highest tertile had a hazard ratio of 0.60 (95% CI, 0.42–
0.87) (p for trend = 0.007). In a follow-up analysis, the Mediterranean diet was also
associated with a reduced risk of developing mild cognitive impairment and of
progression from mild cognitive impairment to AD (Scarmeas et al. 2009).
Physical Activity
Exercise can enhance learning in both young and aged animals (van
Praag et al. 1999), activate brain plasticity mechanisms, remodel neuronal
circuitry in the brain (Cotman and Berchtold 2002), promote brain vascularization
(Black et al. 1990), and stimulate neurogenesis (van Praag et al. 1999). It may also
increase neuronal survival and resistance to brain insults (Carro et al. 2001),
increase levels of brain-derived neurotrophic factor, mobilize gene expression
profiles that would be predicted to benefit brain plasticity (Cotman and Berchtold
2002), and reduce levels of C-reactive protein and interleukin-6, two inflammatory
markers (Ford 2002; Reuben et al. 2003). A Cochrane review (Angevaren et al.
2008) found that eight of 11 random, controlled trials of exercise in older people
without known cognitive impairment reported that aerobic exercise interventions
were associated with improvements in cognitive function.
Although some studies have failed to detect an association between
physical activity and dementia (Wang et al. 2002; Wilson et al. 2002a; Verghese
et al. 2003b), others have observed a beneficial role (Podewils et al. 2005; Rovio
et al. 2005; Larson et al. 2006; Wang et al. 2006). A study of 1880 communitydwelling elders without dementia living in New York City investigated the
combined association of diet and physical activity with Alzheimer risk. A
combination of adherence to a strict Mediterranean-type diet and regular
physical activity (compared with no or minimal physical activity) was associated
with a significant reduction in risk of AD.
Cognitive Enhancement
Several studies have specifically examined the potential effects of
cognitive engagement on the risk of AD (Wilson et al. 2002b, 2007; Verghese et
al. 2003b; Akbaraly et al. 2009). The studies used self-report of the frequency of
involvement in specific activities that potentially have a cognitive component. In
the Three-City cohort study, analyses were carried out on 5698 dementia-free
participants aged 65 and over. Stimulating leisure activities were significantly
associated with a reduced risk of AD (hazard ratio (HR) = 0.39). This finding was
independent of other proxies of cognitive reserve and remained significant after
adjusting for vascular risk factors, depressive symptoms and physical functioning.
GENETIC EPIDEMIOLOGY
Rare Variants
Rare mutations in three genes have been firmly implicated in familial earlyonset disease: APP, PSEN1, and PSEN2 (Table 2; Goate et al. 1991; Levy-Lahad et
al. 1995a,b; Rogaev et al. 1995; Sherrington et al. 1995, 1996). These mutations
have high penetrance, are mostly inherited in an autosomal dominant pattern
and lead with certainty to enhanced relative levels of the Aβ42 peptide, its
aggregation and an early onset of disease, typically beginning in the fourth or
fifth decade of life. APP mutations account for an even smaller fraction (less than
1% of all AD patients). Rare variants such as these are occasionally seen in families
of patients with familial Alzheimer disease having later onset (Athan et al. 2001).
All APP missense mutations influence APP proteolytic processing and/or
aggregation, because they are positioned in or near the Aβ-coding exons (16
and 17) of APP (see AD Mutation Database, http://www.molgen.vibua.be/ADMutations/). The mutation spectrum also includes microduplication at
the APP locus on Ch 21. At the time of writing, 182 different AD-related mutations
in 401 families have been identified in PSEN1, whereas only 14 mutations in 23
families were detected in PSEN2 (http://www.molgen.vib-ua.be/ADMutations/).
The majority of PSEN mutations are single-nucleotide substitutions, but small
deletions and insertions have also been described. PSEN mutations alter the γsecretase-mediated proteolytic cleavage of APP, resulting in an increased
Aβ42/Aβ40 ratio by an increase in Aβ42 and/or a decrease in Aβ40, suggesting a
partial loss-of-function mechanism rather than a gain-of-function in PSEN (see
Tanzi 2011 for a detailed review). Although mutations in these three genes
represent rare causes of AD, their discovery greatly supported a pivotal role for
Aβ in the pathogenesis of AD. According to this amyloid (or Aβ hypothesis),
neurodegenerative processes are the consequence of an imbalance between
Aβ production and Aβ clearance, suggesting that other genes involved in these
pathways might also turn out to be risk factors.
TABLE 2:
Gene
variants
associated
with
Alzheimer disease
Genre
Main alteration
Amyloid
precursor Mutation
protein (APP)
Presenilin 1 (PSEN1)
Mutation
Presenilin 2 (PSEN2)
Mutation
Apolipoprotein-E (APOE)
Common variant
Sortilin-related receptor,
L(DLR class) A repeatscontaining (SORL1)
Clusterin (CLU)
Phosphatidylinositol
binding
clathrin
assembly
protein
(PICALM)
Complement
component
(3b/4b)
receptor 1 (CR1)
Bridging integrator 1
(BIN1)
Common variant
Presumed mechanism
Autosomal
dominant,
mostly early onset
Autosomal
dominant,
mostly early onset
Autosomal
dominant,
mostly early onset
Familial and sporadic,
late onset
Familial and sporadic,
late onset
Common variant
Common variant
Sporadic, late onset
Sporadic, late onset
Common variant
Sporadic, late onset
Common variant
Sporadic, late onset
Common Variants
The strongest common genetic variant for typical late-onset AD beginning
after age approximately 65 years is apolipoprotein E (APOE), a three-allele
polymorphism (ε2, ε3, and ε4) where ε3 is considered a neutral allele, ε4 the highrisk allele, and ε2 a protective allele (Table 2). The ε4 allele influences age at onset
in a dose-dependent manner (Corder et al. 1993). However, more than half of
the patients with late-onset disease do not have the high-risk ε4 allele. The
population attributable risk related to APOE-ε4 has been estimated at 20% (Slooter
et al. 1998). Genome-wide association (GWA) studies have identified variants in
CLU, PICALM, CR1, and BIN1 as putative susceptibility loci (Harold et al. 2009;
Lambert et al. 2009; Seshadri et al. 2010). These genetic variants have been
confirmed in other non-Hispanic and Hispanic populations (Carrasquillo et al.
2010; Jun et al. 2010; Lee et al. 2010). The odds ratios for these genes are much
lower than for APOE (OR = are 3.2 and 14.9 for ε3/ε4 and ε4/ε4, respectively [Farrer
et al. 1997]) and range from 1.16 to 1.20 for CR1, CLU, and PICALM.
Familial Late-Onset Alzheimer Disease
Bertram et al. (2008) performed a GWA study in 1376 samples from 410
families with late-onset Alzheimer disease (LOAD) and subsequently replicated
their findings. A locus on chromosome 14q31 was strongly associated with LOAD,
but the identity of the underlying locus is unknown and may be a modifier of onset
age. The results of GWA studies in the NIA-LOAD Family Study, involving 900+
families stratified by APOE genotype, also identified single-nucleotide
polymorphisms on chromosome 10p14 in CUGBP2 with genome wide significance
within individuals with one APOE ε4 allele, which was replicated in an
independent Caribbean Hispanic cohort (Wijsman et al. 2011). The NIA-LOAD
Family Study also replicated the variants in BIN1 and provided modest
confirmation for CLU, but not for CR1 or PICALM after APOE adjustment
(Hollingworth et al. 2011; Naj et al. 2011). The role of these genes in the
pathogenesis of Alzheimer's disease remains to be determined, but it is clear that
large sample sizes have enabled identification of these putative gene variants.
Finally, variants in SORL1, which encodes a protein involved in trafficking of
APP, are associated with late-onset AD. Although in line with other recently
described genetic links for AD (Lee et al. 2007; Rogaeva et al. 2007), the effect
sizes of the SORL1 associations are modest (Reitz et al. 2011). Variants in the SORL1
homolog, SORCS1, are also modestly associated with AD. Overexpression of either
gene leads to a decrease in Aβ levels in cultured cells, whereas inhibition by RNAi
increases Aβ. Thus, both genes may play a role in AD pathogenesis.
Although these results of the published GWA studies are informative, the
genetic associations need functional validation. GWA studies represent a method
of screening the genome, but limitations exist in their ability to detect true
associations. The results of such studies might be difficult to replicate if the real
effect turns out to be smaller than the effect observed in the initial study. In
addition, GWA studies may not detect associations with multiple rare variants at
a single site (which are better detected by linkage studies) or with single rare
variants (minor allele frequency <5%). Finally, such studies alone cannot prove
causality or establish the biological significance of an observed genetic
association.
Therefore, our understanding of AD pathogenesis has grown substantially
over the past two decades. However, with the large numbers of individuals
reaching the age of highest risk, some would say that we have a long way to go
toward preventing or limiting the full impact of the disease. Current treatments
are palliative at best and newer therapies remain unproven. Knowing who is a risk
and why will make prevention and management easier in the future
Diagnosis of Alzheimer’s Disease
A key component of a diagnostic assessment is self-reporting about
symptoms, as well as the information that a close family member or friend can
provide about symptoms and their impact on daily life. Additionally, a diagnosis
of Alzheimer's disease is based on tests your doctor administers to assess memory
and thinking skills.
Laboratory and imaging tests can rule out other potential causes or help
the doctor better characterize the disease-causing dementia symptoms.
The entire set of diagnostic tools is designed to detect dementia and
determine with relatively high accuracy whether Alzheimer's disease or another
condition is the cause. Alzheimer's disease can be diagnosed with complete
certainty after death, when microscopic examination of the brain reveals the
characteristic plaques and tangles.
Tests
A diagnostic work-up would likely include the following tests:
Physical and neurological exam
Your doctor will perform a physical exam and likely assess overall neurological
health by testing the following:






Reflexes
Muscle tone and strength
Ability to get up from a chair and walk across the room
Sense of sight and hearing
Coordination
Balance
Lab tests
Blood tests may help your doctor rule out other potential causes of memory
loss and confusion, such as a thyroid disorder or vitamin deficiencies.
Mental status and neuropsychological testing
Your doctor may conduct a brief mental status test or a more extensive set
of tests to assess memory and other thinking skills. Longer forms of
neuropsychological testing may provide additional details about mental function
compared with people of a similar age and education level. These tests are also
important for establishing a starting point to track the progression of symptoms in
the future.
Brain imaging
Images of the brain are now used chiefly to pinpoint visible abnormalities
related to conditions other than Alzheimer's disease — such as strokes, trauma or
tumors — that may cause cognitive change. New imaging applications —
currently used primarily in major medical centers or in clinical trials — may enable
doctors to detect specific brain changes caused by Alzheimer's.
Imaging of brain structures include the following:
Magnetic resonance imaging (MRI). MRI uses radio waves and a strong
magnetic field to produce detailed images of the brain. MRI scans are used
primarily to rule out other conditions. While they may show brain shrinkage, the
information doesn't currently add significant value to making a diagnosis.
Computerized tomography (CT). A CT scan, a specialized X-ray technology,
produces cross-sectional images (slices) of your brain. It's currently used chiefly to
rule out tumors, strokes and head injuries.
Imaging of disease processes can be performed with positron emission
tomography (PET). During a PET scan, a low-level radioactive tracer is injected
into the blood to reveal a particular feature in the brain. PET imaging may include
the following:



Fluorodeoxyglucose (FDG) PET scans show areas of the brain in which
nutrients are poorly metabolized. Identifying patterns of degeneration —
areas of low metabolism — can help distinguish between Alzheimer's
disease and other types of dementia.
Amyloid PET imaging can measure the burden of amyloid deposits in the
brain. This imaging is primarily used in research but may be used if a
person has unusual or very early onset of dementia symptoms.
Tau Pet imaging, which measures the burden of neurofibrillary tangles in
the brain, is only used in research.
In special circumstances, such as rapidly progressive dementia or very early onset
dementia, other tests may be used to measure abnormal beta-amyloid or tau in
the cerebrospinal fluid.
Future diagnostic tests
Researchers are working on tests that can measure the biological evidence
of disease processes in the brain. These tests may improve the accuracy of
diagnoses and enable earlier diagnosis before the onset of symptoms.
Genetic testing generally isn't recommended for a routine Alzheimer's
disease evaluation. The exception is people who have a family history of earlyonset Alzheimer's disease. Meeting with a genetic counselor to discuss the risks
and benefits of genetic testing is recommended before undergoing any tests.
Treatments for Alzheimer’s Disease
Drugs
Current Alzheimer's medications can help for a time with memory
symptoms and other cognitive changes. Two types of drugs are currently used to
treat cognitive symptoms:

Cholinesterase inhibitors. These drugs work by boosting levels of cellto-cell communication by preserving a chemical messenger that is
depleted in the brain by Alzheimer's disease. The improvement is
modest.
Cholinesterase inhibitors may also improve neuropsychiatric symptoms,
such as agitation or depression. Commonly prescribed cholinesterase inhibitors
include donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon).
The main side effects of these drugs include diarrhea, nausea, loss of
appetite and sleep disturbances. In people with cardiac conduction disorders,
serious side effects may include cardiac arrhythmia.

Memantine (Namenda). This drug works in another brain cell
communication network and slows the progression of symptoms
with moderate to severe Alzheimer's disease. It's sometimes used in
combination with a cholinesterase inhibitor. Relatively rare side
effects include dizziness and confusion.
Sometimes other medications such as antidepressants may be prescribed
to help control the behavioral symptoms associated with Alzheimer's disease.
Creating a safe and supportive environment
Adapting the living situation to the needs of a person with Alzheimer's
disease is an important part of any treatment plan. For someone with Alzheimer's,
establishing and strengthening routine habits and minimizing memorydemanding tasks can make life much easier.
You can take these steps to support a person's sense of well-being and continued
ability to function:
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Always keep keys, wallets, mobile phones and other valuables in the
same place at home, so they don't become lost.
Keep medications in a secure location. Use a daily checklist to keep
track of dosages.
Arrange for finances to be on automatic payment and automatic
deposit.
Carry a mobile phone with location capability so that a caregiver
can track its location. Program important phone numbers into the
phone.
Make sure regular appointments are on the same day at the same
time as much as possible.
Use a calendar or whiteboard in the home to track daily schedules.
Build the habit of checking off completed items.
Remove excess furniture, clutter and throw rugs.
Install sturdy handrails on stairways and in bathrooms.
Ensure that shoes and slippers are comfortable and provide good
traction.
Reduce the number of mirrors. People with Alzheimer's may find
images in mirrors confusing or frightening.
Make sure that the person with Alzheimer's carries identification or
wears a medical alert bracelet.
Keep photographs and other meaningful objects around the house.
Alternative medicine
Various herbal remedies, vitamins and other supplements are widely
promoted as preparations that may support cognitive health or prevent or delay
Alzheimer's. Clinical trials have produced mixed results with little evidence to
support them as effective treatments.
Some of the treatments that have been studied recently include:
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Omega-3 fatty acids. Omega-3 fatty acids in fish or from supplements
may lower the risk of developing dementia, but clinical studies have
shown no benefit for treating Alzheimer's disease symptoms.
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Curcumin. This herb comes from turmeric and has anti-inflammatory and
antioxidant properties that might affect chemical processes in the brain.
So far, clinical trials have found no benefit for treating Alzheimer's disease.
Ginkgo. Ginkgo is a plant extract containing several medicinal
properties. A large study funded by the National Institutes of Health found
no effect in preventing or delaying Alzheimer's disease.
Vitamin E. Although vitamin E isn't effective for preventing Alzheimer's,
taking 2,000 international units daily may help delay the progression in
people who already have the disease. However, study results have been
mixed, with only some showing this benefit. Further research into the
safety of 2,000 international units daily of Vitamin E in a dementia
population will be needed before it can be routinely recommended.
Supplements promoted for cognitive health can interact with medications
you're taking for Alzheimer's disease or other health conditions. Work closely with
your health care team to create a safe treatment plan with any prescriptions,
over-the-counter medications or dietary supplements.
Lifestyle and home remedies
Healthy lifestyle choices promote good overall health and may play a role
in maintaining cognitive health.
Exercise
Regular exercise is an important part of a treatment plan. Activities such as
a daily walk can help improve mood and maintain the health of joints, muscles
and the heart. Exercise can also promote restful sleep and prevent constipation.
People with Alzheimer's who develop trouble walking may still be able to
use a stationary bike or participate in chair exercises. You may find exercise
programs geared to older adults on TV or on DVDs.
Nutrition
People with Alzheimer's may forget to eat, lose interest in preparing meals
or not eat a healthy combination of foods. They may also forget to drink enough,
leading to dehydration and constipation.
Offer the following:
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Healthy options. Buy healthy food options that the person with
Alzheimer's disease likes and can eat.
Water and other healthy beverages. Try to ensure that a person with
Alzheimer's drinks several glasses of liquids every day. Avoid beverages
with caffeine, which can increase restlessness, interfere with sleep and
trigger a frequent need to urinate.
High-calorie, healthy shakes and smoothies. You can supplement
milkshakes with protein powders or make smoothies featuring favorite
ingredients. This may be particularly important when eating becomes
more difficult.
Social engagement and activities
Social interactions and activities can support the abilities and skills that are
preserved. Doing things that are meaningful and enjoyable are important for the
overall well-being of a person with Alzheimer's disease.
These might include:
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Listening to music or dancing
Reading or listening to books
Gardening or crafts
Social events at senior or memory care centers
Planned activities with children
Coping and support
People with Alzheimer's disease experience a mixture of emotions —
confusion, frustration, anger, fear, uncertainty, grief and depression.
If you're caring for someone with Alzheimer's, you can help them cope with
the disease by being there to listen, reassuring the person that life can still be
enjoyed, providing support, and doing your best to help the person retain dignity
and self-respect.
A calm and stable home environment can help reduce behavior problems.
New situations, noise, large groups of people, being rushed or pressed to
remember, or being asked to do complicated tasks can cause anxiety. As a
person with Alzheimer's becomes upset, the ability to think clearly declines even
more.
Caring for the caregiver
Caring for a person with Alzheimer's disease is physically and emotionally
demanding. Feelings of anger and guilt, stress and discouragement, worry and
grief, and social isolation are common.
Caregiving can even take a toll on the caregiver's physical health. Paying
attention to your own needs and well-being is one of the most important things
you can do for yourself and for the person with Alzheimer's.
If you're a caregiver for someone with Alzheimer's, you can help yourself by:
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Learning as much about the disease as you can
Asking questions of doctors, social workers and others involved in
the care of your loved one
Calling on friends or other family members for help when you need
it
Taking a break every day
Spending time with your friends
Taking care of your health by seeing your own doctors on
schedule, eating healthy meals and getting exercise
Joining a support group
Making use of a local adult day center, if possible
Many people with Alzheimer's and their families benefit from counseling or
local support services. Contact your local Alzheimer's Association affiliate to
connect with support groups, doctors, occupational therapists, resources and
referrals, home care agencies, residential care facilities, a telephone help line,
and educational seminars.
Preparing for your appointment
Medical care for the loss of memory or other thinking skills usually requires a
team or partner strategy. If you are concerned about your memory loss or related
symptoms, ask a close relative or friend to go with you to a doctor's appointment.
In addition to providing support, your partner can provide help in answering
questions.
If you are accompanying someone on a doctor's appointment, your role
may be to provide some history or your perspective on changes you have
observed. This teamwork is an important part of medical care for initial
appointments and throughout a treatment plan.
Your primary care doctor may refer you to a neurologist, psychiatrist,
neuropsychologist or other specialist for further evaluation.
Alzheimer's disease complications
Restlessness and agitation
People diagnosed with AD commonly have periods of agitation and
anxiousness. A loved one’s ability to reason and understand certain situations can
also decline as the disease progresses. If they can’t make sense of a confusing
world, they can become fearful and agitated.
You can do things to help a loved one feel safe and calm. You can start by
providing a safe environment and removing any stressors that could cause
agitation, such as loud noise. Some people with AD also become agitated when
their physically uncomfortable. Their agitation might increase if they’re unable to
speak or express how they feel. Take steps to make sure their pain, hunger, and
thirst levels remain at a comfortable level. You can also calm agitation by
reassuring them that they’re safe.
Bladder and bowel problems
Bladder and bowel problems are other complications of AD. As the disease
progresses, a loved one may no longer recognize the sensation of needing to use
the bathroom. They may also be unable to respond quickly to urges. This can result
from limited mobility or limited communication skills. A loved one may also
become confused and use the restroom in inappropriate places, but you can
help them cope.
If possible, remind your loved one to use the bathroom and offer help. You
can also make it easier for them to get to the bathroom alone. Make sure they
can easily remove clothing and install night lights to ensure they get to the
bathroom safely at night.
If mobility is an issue, your loved one may appreciate a commode near
their bed or undergarments for incontinence.
Depression
Some people with AD also have depression and don’t know how to cope
with a loss of cognitive functions. The symptoms of depression may include:
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sleeping problems
changes in mood
withdrawing from friends and relatives
difficulty concentrating
The symptoms of depression can be similar to the general symptoms of AD.
This can make it difficult to determine whether your loved one is experiencing
depression or just the normal symptoms of AD. A doctor can refer your loved one
to a geriatric psychiatrist to make this determination.
Treatment options for depression in people with AD include attending
support groups and speaking with a therapist. Speaking to others with AD can
also be helpful. Getting regular exercise and participating in activities they enjoy
can also improve their mental outlook. In some cases, a doctor may recommend
antidepressants.
Falls
AD can also affect balance and coordination. The risk of falling increases
as the disease worsens. This can lead to head trauma and broken bones.
You can reduce your loved one’s risk of falling by assisting them as they
walk and making sure pathways are clear in their home. Some people with AD
doesn’t want to lose their independence. In this case, you might suggest walking
aids to help them maintain their balance. If a loved one is home alone, get a
medical alert device so they can contact emergency services if they fall and
can’t get to a phone.
Infections
AD can cause your loved one to lose control of normal body functions, and
they may forget how to chew food and swallow. If this happens, they have an
increased risk of inhaling food and drinks. This can cause pulmonary aspiration
and pneumonia, which can be life-threatening.
You can help someone avoid this complication by making sure they eat
and drink while sitting up with their head elevated. You can also cut their food
into bite-size pieces to make swallowing easier. The symptoms of pneumonia
include:
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a fever
a cough
shortness of breath
excess phlegm
Pneumonia and other respiratory infections need medical treatment with
antibiotics. If you notice that your loved one coughs after drinking, you should
alert their doctor who may refer them to a speech therapist for further evaluation.
Wandering
Wandering is another common complication of AD. People with AD can
experience restlessness and sleeplessness due to disruption in their normal sleep
patterns. As a result, they may wander out of the home believing that they’re
running an errand or going to work. The problem, however, is that a loved one
may leave home and forget their way back. Some people with AD wander from
home at night when everyone is asleep.
Make sure your loved one wears a medical alert bracelet with:
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their name
their address
their phone number
your contact information
You can also keep loved ones safe by installing an alarm system, deadbolts,
and bells on the door.
Malnutrition and dehydration
It's important that your loved one eats and drinks enough fluids. However,
this can be difficult because they may refuse to eat or drink as the disease
progresses. Also, they may be unable to consume food and drinks because of
difficulty swallowing.
The symptoms of dehydration include:
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a dry mouth
headaches
dry skin
sleepiness
irritability
Your loved one may be malnourished if they’re losing weight, they have
frequent infections, or they experience changes in their level of consciousness.
Visit during mealtimes and help with preparing meals to ensure they don't
experience dehydration or malnutrition. Observe your loved one eating and
drinking to ensure they consume plenty of fluids. This includes water and other
beverages, such as juice, milk, and tea. If you’re concerned about dehydration
or malnutrition, speak with their doctor.
Preventions for Alzheimer’s Disease
Pillar #1: Regular exercise
According to the Alzheimer’s Research & Prevention Foundation, regular
physical exercise can reduce your risk of developing Alzheimer’s disease by up to
50 percent. What’s more, exercise can also slow further deterioration in those who
have already started to develop cognitive problems. Exercise protects against
Alzheimer’s and other types of dementia by stimulating the brain’s ability to
maintain old connections as well as make new ones.
Aim for at least 150 minutes of moderate intensity exercise each week. The
ideal plan involves a combination of cardio exercise and strength training. Good
activities for beginners include walking and swimming.
Build muscle to pump up your brain. Moderate levels of weight and
resistance training not only increase muscle mass, they help you maintain brain
health. For those over 65, adding 2-3 strength sessions to your weekly routine may
cut your risk of Alzheimer’s in half.
Include balance and coordination exercises. Head injuries from falls are an
increasing risk as you age, which in turn increase your risk for Alzheimer’s disease
and dementia. Balance and coordination exercises can help you stay agile and
avoid spills. Try yoga, Tai Chi, or exercises using balance balls.
Pillar #2: Social engagement
Human beings are highly social creatures. We don’t thrive in isolation, and
neither do our brains. Staying socially engaged may even protect against
Alzheimer’s disease and dementia in later life, so make developing and
maintaining a strong network of friends a priority.
You don’t need to be a social butterfly or the life of the party, but you do
need to regularly connect face-to-face with someone who cares about you and
makes you feel heard. While many of us become more isolated as we get older,
it’s never too late to meet others and develop new friendships:
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Volunteer
Join a club or social group
Visit your local community center or senior center
Take group classes (such as at the gym or a community college)
Reach out over the phone or email
Connect to others via social networks such as Facebook
Get to know your neighbors
Make a weekly date with friends
Get out (go to the movies, the park, museums, and other public places)
Pillar #3: Healthy diet
In Alzheimer’s disease, inflammation and insulin resistance injure neurons
and inhibit communication between brain cells. Alzheimer’s is sometimes
described as “diabetes of the brain,” and a growing body of research suggests a
strong link between metabolic disorders and the signal processing systems. By
adjusting your eating habits, however, you can help reduce inflammation and
protect your brain.
Cut down on sugar. Sugary foods and refined carbs such as white flour,
white rice, and pasta can lead to dramatic spikes in blood sugar which inflame
your brain. Watch out for hidden sugar in all kinds of packaged foods from cereals
and bread to pasta sauce and low or no-fat products.
Enjoy a Mediterranean diet. Several epidemiological studies show that
eating a Mediterranean diet dramatically reduces the risk of cognitive
impairment and Alzheimer’s disease. That means plenty of vegetables, beans,
whole grains, fish and olive oil—and limited processed food.
Avoid trans fats. These fats can cause inflammation and produce free
radicals—both of which are hard on the brain. Reduce your consumption by
avoiding fast food, fried and packaged foods, and anything that contains
“partially hydrogenated oils,” even if it claims to be trans fat-free.
Get plenty of omega-3 fats. Evidence suggests that the DHA found in these
healthy fats may help prevent Alzheimer’s disease and dementia by reducing
beta-amyloid plaques. Food sources include cold-water fish such as salmon, tuna,
trout, mackerel, seaweed, and sardines. You can also supplement with fish oil.
Stock up on fruit and vegetables. When it comes to fruits and vegetables,
the more the better. Eat up across the color spectrum to maximize protective
antioxidants and vitamins, including green leafy vegetables, berries, and
cruciferous vegetables such as broccoli.
Enjoy daily cups of tea. Regular consumption of great tea may enhance
memory and mental alertness and slow brain aging. White and oolong teas are
also particularly brain healthy. Drinking 2-4 cups daily has proven benefits.
Although not as powerful as tea, coffee also confers brain benefits.
Cook at home often. By cooking at home, you can ensure that you’re
eating fresh, wholesome meals that are high in brain-healthy nutrients and low in
sugar, salt, unhealthy fat, and additives.
Pillar #4: Mental stimulation
Those who continue learning new things and challenging their brains
throughout life are less likely to develop Alzheimer’s disease and dementia. In
essence, you need to “use it or lose it.” In the groundbreaking NIH ACTIVE study,
older adults who received as few as 10 sessions of mental training not only
improved their cognitive functioning in daily activities in the months after the
training, but continued to show long-lasting improvements 10 years later.
Activities involving multiple tasks or requiring communication, interaction,
and organization offer the greatest protection. Set aside time each day to
stimulate your brain:
Learn something new. Study a foreign language, practice a musical
instrument, learn to paint or sew, or read the newspaper or a good book. One of
the best ways to take up a new hobby is to sign up for a class and then schedule
regular times for practicing. The greater the novelty, complexity, and challenge,
the greater the benefit.
Raise the bar for an existing activity. If you’re not keen on learning
something new, you can still challenge your brain by increasing your skills and
knowledge of something you already do. For example, if you can play the piano
and don’t want to learn a new instrument, commit to learning a new piece of
music or improving how well you play your favorite piece. Or if you’re a golfer,
aim to lower your handicap.
Practice memorization. Start with something short, progressing to something
a little more involved, such as the 50 U.S. state capitals. Create rhymes and
patterns to strengthen your memory connections.
Enjoy strategy games, puzzles, and riddles. Brain teasers and strategy
games provide a great mental workout and build your capacity to form and
retain cognitive associations. Do a crossword puzzle, play board games, cards, or
word and number games such as Scrabble or Sudoku.
Practice the 5 W’s. Observe and report like a crime detective. Keep a “Who,
What, Where, When, and Why” list of your daily experiences. Capturing visual
details keeps your neurons firing.
Follow the road less traveled. Take a new route, eat with your non-dominant
hand, rearrange your computer file system. Vary your habits regularly to create
new brain pathways.
Pillar #5: Quality sleep
It’s common for people with Alzheimer’s disease to suffer from insomnia and
other sleep problems. But new research suggests that disrupted sleep isn’t just a
symptom of Alzheimer’s, but a possible risk factor. An increasing number of studies
have linked poor sleep to higher levels of beta-amyloid, a sticky brain-clogging
protein that in turn further interferes with sleep—especially with the deep sleep
necessary for memory formation. Other studies emphasize the importance of
uninterrupted sleep for flushing out brain toxins.
If nightly sleep deprivation is slowing your thinking and affecting your mood,
you may be at greater risk of developing symptoms of Alzheimer’s disease. The
vast majority of adults need at least 8 hours of sleep per night.
Get screened for sleep apnea. If you’ve received complaints about your
snoring, you may want to get tested for sleep apnea, a potentially dangerous
condition where breathing is disrupted during sleep. Treatment can make a huge
difference in both your health and sleep quality.
Establish a regular sleep schedule. Going to bed and getting up at the
same time reinforces your natural circadian rhythms. Your brain’s clock responds
to regularity.
Be smart about napping. While taking a nap can be a great way to
recharge, especially for older adults, it can make insomnia worse. If insomnia is a
problem for you, consider eliminating napping. If you must nap, do it in the early
afternoon, and limit it to thirty minutes.
Set the mood. Reserve your bed for sleep and sex, and ban television and
computers from the bedroom (both are stimulating and may lead to difficulties
falling asleep).
Create a relaxing bedtime ritual. Take a hot bath, do some light stretches,
write in your journal, or dim the lights. As it becomes habit, your nightly ritual will
send a powerful signal to your brain that it’s time for deep restorative sleep.
Quiet your inner chatter. When stress, anxiety, or negative internal dialogues
keep you awake, get out of bed. Try reading or relaxing in another room for
twenty minutes then hop back in.
Pillar #6: Stress management
Chronic or persistent stress can take a heavy toll on the brain, leading to
shrinkage in a key memory area, hampering nerve cell growth, and increasing
the risk of Alzheimer’s disease and dementia. Yet simple stress management tools
can minimize its harmful effects.
Breathe! Quiet your stress response with deep, abdominal breathing.
Restorative breathing is powerful, simple, and free!
Schedule daily relaxation activities. Keeping stress under control requires
regular effort. Make relaxation a priority, whether it’s a walk in the park, playtime
with your dog, yoga, or a soothing bath.
Nourish inner peace. Regular meditation, prayer, reflection, and religious
practice may immunize you against the damaging effects of stress.
Make fun a priority. All work and no play is not good for your stress levels or
your brain. Make time for leisure activities that bring you joy, whether it be
stargazing, playing the piano, or working on your bike.
Keep your sense of humor. This includes the ability to laugh at yourself. The
act of laughing helps your body fight stress.
Other tips to reduce the risk of Alzheimer’s:
Just as what’s good for the body is also good for the brain, so too is the
converse: what’s bad for the body is bad for the brain.
Stop smoking. Smoking is one of the most preventable risk factors for
Alzheimer’s disease and dementia. One study found that smokers over the age
of 65 have a nearly 80% higher risk of Alzheimer’s than those who have never
smoked. When you stop smoking, the brain benefits from improved circulation
almost immediately.
Control blood pressure and cholesterol levels. Both high blood pressure and
high total cholesterol are associated with an increased risk of Alzheimer’s disease
and vascular dementia. Improving those numbers are good for your brain as well
as your heart.
Watch your weight. Extra pounds are a risk factor for Alzheimer’s disease
and other types of dementia. A major study found that people who were
overweight in midlife were twice as likely to develop Alzheimer’s down the line,
and those who were obese had three times the risk. Losing weight can go a long
way to protecting your brain.
Drink only in moderation. While there appear to be brain benefits in
consuming red wine in moderation, heavy alcohol consumption can dramatically
raise the risk of Alzheimer’s and accelerate brain aging.
Sources:
https://www.brightfocus.org/alzheimers/article/history-alzheimers-disease
https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/symptomscauses/syc-20350447
https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease
https://www.nia.nih.gov/health/what-causes-alzheimers-disease
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405821/
https://www.mayoclinic.org/diseases-conditions/alzheimers-disease/diagnosistreatment/drc-20350453
https://www.healthline.com/health/alzheimers-diseasecomplications#complications
Prepared By:
Angel Janelle D. King
Krisleen B. Estrella