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Alzheimer's disease (AD), a neurodegenerative
disease, is the most common cause of dementia and
characterized clinically by progressive intellectual
deterioration together with declining activities of daily
living and neuropsychiatric symptoms or behavioral changes.
The most striking early symptom is memory loss (amnesia),
usually manifest as minor forgetfulness that becomes
steadily denser with illness progression, with relative
preservation of older memories. As the disorder progresses,
cognitive (intellectual) impairment extends to the domains
of language (aphasia), coordinated movement (apraxia),
recognition (agnosia) and those functions (such as
decision-making and planning) closely related to the frontal
lobe of the brain, reflecting extension of the underlying
pathological process. This consists principally of neuronal
(cell) loss (or atrophy), together with deposition of
amyloid plaques and neurofibrillary tangles. Genetic factors
are known to be important, and polymorphisms (variations) in
three different autosomal dominant genes - Presenilin 1,
Presenilin 2, and Amyloid Precursor Protein - have been
identified that account for a small number of cases of
familial, early-onset AD. For late onset AD (LOAD), only one
susceptibility gene has so far been identified - the epsilon
4 allele of the APOE gene. Age of onset itself has a
heritability of around 50%.
History
The symptoms of the disease as
a distinct entity were first identified by Emil Kraepelin,
and the characteristic neuropathology was first observed by
Alois Alzheimer, a German psychiatrist, in 1906. In this
sense, the disease was co-discovered by Kraepelin and
Alzheimer, who worked in Kraepelin's laboratory. Because of
the overwhelming importance Kraepelin attached to finding
the neuropathological basis of psychiatric disorders,
Kraepelin made the generous decision that the disease would
bear Alzheimer's name (J. Psychiat. Res., 1997, Vol 31, No.
6, pp. 635-643).
For most of the twentieth century, the diagnosis of
Alzheimer's disease was reserved for individuals between the
ages of 45-65 who developed symptoms of presenile dementia,
which was considered to be a more or less normal outcome of
the aging process. In the 1970s and early 1980s, however,
the name "Alzheimer's disease" began to be used, within and
outside the medical profession, equally for individuals age
65 and older with senile dementia, and was eventually
adopted formally for all individuals with the common symptom
pattern and disease course in the psychiatric and
neurological nomenclature.Clinical
features
The usual
first symptom noticed is memory loss which progresses from
seemingly simple and often fluctuating forgetfulness (with
which the disease should not be confused) to a more
pervasive loss of recent memory, then of familiar and
well-known skills or objects or persons. Aphasia,
disorientation and disinhibition usually accompany the loss
of memory. Alzheimer's disease may also include behavioral
changes, such as outbursts of violence or excessive
passivity in people who have no previous history of such
behavior. In the later stages, deterioration of musculature
and mobility, leading to bedfastness, inability to feed
oneself, and incontinence, will be seen if death from some
external cause (e.g. heart attack or pneumonia) does not
intervene. Average duration of the disease is approximately
7-10 years, although cases are known where reaching the
final stage occurs within 4-5 years, or up to 25 years.
Diagnosis
The
diagnosis is made primarily by clinical observation and
tests of memory and intellectual functioning over a series
of weeks or months, with various physical tests (blood tests
and neuroimaging) being performed to rule out alternative
diagnoses. No medical tests are available to conclusively
diagnose Alzheimer's disease pre-mortem, however.
Interviews with family members and/or caregivers can be
extremely important in the early phases as well, as the
sufferer him/herself may tend to minimize his symptomatology
or may be being observed on a day when his/her symptoms are
in temporary dormancy.
Initial suspicion of dementia may be strengthened by
performing the mini mental state examination, after
excluding clinical depression. Psychological testing
generally focuses on memory, attention, abstract thinking,
the ability to name objects, and other cognitive functions.
Results of psychological tests do not easily distinguish
between Alzheimer's disease and other types of dementia but
can be helpful in establishing the presence of and severity
of dementia. They can also be useful in distinguishing true
dementia from temporary (and more treatable) cognitive
impairment due to depression or psychosis, which has
sometimes been termed "pseudodementia".
While expert clinicians who specialize in memory disorders
can now diagnose AD with an accuracy of 85-90%, a definitive
diagnosis of Alzheimer's disease must await the autopsy.
Pathology
Microscopy
There are
several changes found in the brain in AD (in order of
appearance):
-
The
deposition of an abnormal protein (amyloid beta) outside
nerve cells in the form of amyloid. These are called
diffuse plaques and amyloid also forms the core of more
organized plaques called senile or neuritic plaques.
Recently evidence has begun to accumulate implicating
simpler, soluble forms of amyloid (oligomers) in the
pathological process, and the presence of plaque amyloid
does not correlate well with the degree of dementia.
Amyloid also accumulates in the walls of small blood
vessels in the brain. This is termed amyloid angiopathy
(also called congophilic angiopathy). Another pathological
feature of AD is the accumulation of abnormal protein
filaments inside nerve cells in the brain, formed from
aggregation of tau protein, which is normally present to
stabilise microtubules. In AD, an abnormally
phosphorylated form of tau protein accumulates as paired
helical filaments. Tau accumulates in various forms:
-
As
masses of filaments inside nerve cell body termed
neurofibrillary tangles
-
Inside
nerve cell processes in the brain termed
neuropil threads
-
Inside
nerve cell processes that surround amyloid plaques -
termed dystrophic
neurites or plaque neurites.
General
non-specific findings include:
-
Diffuse
neuropathology, nerve cells, their processes, and synapses
are lost from key brain regions. This results in atrophy
of the affected areas and enlargement of the ventricles.
-
Loss of
synaptic contacts between neurons may be related to
disruption of axonal transport and to the dysregulation of
cell adhesion proteins by presenilins. The presenilins
have been identified as part of the processing pathways
that produce the amyloid beta protein.
Neurochemistry
The
neurotransmitters serotonin, acetylcholine, norepinephrine,
and somatostatin are at decreased levels. Glutamate levels
are usually elevated.
Disease
mechanism
Three major
competing hypotheses exist to explain the cause of the
disease.
The oldest
hypothesis is the "cholinergic hypothesis". It states that
Alzheimer's begins as a deficiency in the production of
acetylcholine, a vital neurotransmitter. Much early
therapeutic research was based on this hypothesis, including
restoration of the "cholinergic nuclei". The possibility of
cell-replacement therapy was investigated on the basis of
this hypothesis. All of the first-generation
anti-Alzheimer's medications are based on this hypothesis
and work to preserve acetylcholine by inhibiting
acetylcholinesterases (enzymes that break down
acetylcholine). These medications, though sometimes
beneficial, have not led to a cure. In all cases, they have
served to only treat symptoms of the disease and have
neither halted nor reversed it. These results and other
research have led to the conclusion that acetylcholine
deficiencies may not be directly causal, but are a result of
widespread brain tissue damage, damage so widespread that
cell-replacement therapies are likely to be impractical.
The other
two hypotheses each have their advocates, and have often
been described (lightheartedly) as the "tau-ist" and "ba-ptist"
viewpoints in scientific publications by Alzheimer's disease
researchers. "Tau-ists" believe that the tau protein
abnormalities come first and lead to a full disease cascade.
"bA-ptists" believe that beta amyloid deposits are the
causative factor in the disease. For example, the presence
of the APP gene on chromosome 21 is believed to explain the
high incidence of early-onset AD pathology in patients with
Down syndrome, who carry three copies of chromosome 21 and
thus APP itself. The "ba-ptist" theory is finding new
supporters due to recent discoveries of impaired vascular
and cerebrospinal fluid transport of beta amyloid out of the
brain tissues, resulting in a greater risk for plaque
formation. A third protein, alpha synuclein, which has
already been shown to be important in Parkinson's disease,
has also been demonstrated to be associated with amyloid
plaques in AD. This hypothesis has been given the name "syn-ners"
among AD researchers. There is also a "triple lesion"
hypothesis that proposes a pathological interaction among
these three candidate proteins. The extent of each protein's
contribution may determine whether or not the "lesion
disorder" manifests as AD, Parkinsonism, or other
degenerative diseases.
The presence of plaques and tangles, however, does not
always correlate perfectly with clinical Alzheimer's; in
other words, not all people who have plaques and/or tangles
manifest symptoms of the disease. Loss of synapses
correlates much better with the decline of cognition than
the presence of plaques and tangles. Some recent research is
focusing on the possibility that plaques and tangles arise
as a defense against another, as yet undiscovered, process
or substance that itself causes the disease. Researchers are
intrigued by the idea that the plaques and tangles might not
be the problem, but rather a symptom of the problem. The
plaques and neurofibrillary tangles might be doing an
adequate job of "containing" the disease until they simply
are overwhelmed.
Genetics of
AD
There is
compelling evidence that genetic predisposition underlies
the development of Alzheimer's disease. Rare cases are
caused by dominant genes that run in families. These cases
often have an early age of onset. Mutations in presenilin-1
or presenilin-2 genes have been documented in some families.
Mutations of presenilin 1 (PS1) lead to the most aggressive
form of familial AD (FAD). Evidence from rodent studies
suggests that the FAD mutation of PS1 results in impared
hippocampal-dependent learning which is correlated with
reduced adult neurogenesis in the dentate gyrus [1]).
Mutations in the APP gene on chromosome 21 can also cause
early onset disease.
Unfortunately, the most obviously genetic cases are also the
rarest. Most cases identified are "sporadic" with no clear
family history. It is probable that environmental factors
have to interact with a genetic susceptibility to cause
development of disease. Head injury has been consistently
shown to be linked to later development of AD in
epidemiological studies. In addition, small cranial diameter
has been shown to correlate well with early onset of
recognizable symptoms. The most commonly accepted
explanation for this last feature is that larger brains
simply may have more cells that can afford to be lost.
Inheritance of the epsilon 4 allele of the ApoE gene is
regarded as a risk factor for development of disease, but
large-scale genetic association studies raise the
possibility that even this does not indicate susceptibility
so much as how early one is likely to develop Alzheimer's.
There is speculation among genetic experts that there are
other risk and protective factor genes that may influence
the development of late onset Alzheimer's disease (LOAD).
Intriguing work is currently going on investigating the
possibility that the regulatory regions of various
Alzheimer's associated genes could be important in sporadic
Alzheimer's, especially inflammatory activation of these
genes. These hypotheses include the amyloid beta precursor
protein [2], the beta secretase enzymes [3],
insulin-degrading enzyme [4], endothelin-converting enzymes
[5], and inflammatory 5-lipoxygenase gene [6].
Environmental Conditions
Studies have
not shown strong link with toxins, vitamins, metals or diet,
although rabbits fed a high-cholesterol diet in the presence
of copper ions in their water did develop amyloid brain
lesions and cognitive deficiencies [7], [8]. Likewise,
linkage has been found between zinc or copper and reactive
oxidative stress contributing to Alzheimer's pathology [9],
and the amyloid precursor protein has been shown to alter
expression in response to metal supplementation and
chelation [10], [11], [12]. Therefore, it is hasty and
premature to dismiss any and all environmental effects out
of hand. There have been studies that link aluminium to the
progression of Alzheimer's, but the results from these
studies have not been confirmed and are not widely accepted
by Alzheimer's experts.
Genetic linkage
Alzheimer's
disease is linked to the 1st, 10th, 14th, 9th, 19th, and/or
21st chromosomes, among others. While some genes
predisposing to AD have been identified, most cases are
sporadic. However, sporadic AD most often involves some form
of genetic susceptibility.
Epidemiology
Alzheimer's
disease is the most frequent type of dementia in the elderly
and affects almost half of all patients with dementia.
2-3% of
persons aged 65 show signs of the disease, while 25 - 50% of
persons aged 85 have symptoms of Alzheimer's and an even
greater number have some of the pathological hallmarks of
the disease without the characteristic symptoms. The
proportion of persons with Alzheimer's begins to decrease
after age 85 because of the increased mortality due to the
disease, and relatively few people over the age of 100 have
the disease.
Prevention
Efforts to
find effective treatments for Alzheimer's after-the-fact
have so far been disappointing. Age is the primary risk
factor for Alzheimer's. The baby boom is approaching its
golden years. Indeed, much of the concern about the solvency
of governmental social safety nets is founded on estimates
of the costs of caring for baby boomers, assuming that they
develop Alzheimer's in the same proportions as earlier
generations.
One study ("Leisure Activities and the Risk of Dementia in
the Elderly," New England Journal of Medicine [13]) found
that people who played chess on a regular basis went on to
get Alzheimer's at a substantially lower rate than the
general population. The chess relationship was stronger than
any other factor, including dancing and solving crossword
puzzles, both of which were also shown to be inversely
proportional to getting Alzheimer's disease.
In a number of retrospective studies, regular physical
exercise has appeared to be inversely related to the
development of Alzheimer’s. The Alzheimer's risk of those
exercising regularly was half that of the least active. This
research is consistent with the observation that virtually
all measures designed to promote cardiac fitness and reduce
stroke risk also seem to reduce Alzheimer's risk. However in
one study, dance appeared to be the only exercise effective
in reducing risk. One explanation is that dancing requires
the use of complex mental skills such as performing correct
steps while at the same time keeping track of the music. The
presence of cardiovascular risk factors -- diabetes,
hypertension, high cholesterol and smoking -- in middle age
(ages 40 to 44) was found very strongly associated with
late-life dementia (Neurology 2005;64:277-281. PMID
15668425).
Some studies have indicated that non-steroidal
anti-inflammatory drugs (NSAIDs) like ibuprofen and aspirin
may delay the onset, and lower the ultimate risk, of
Alzheimer’s disease. According to population studies, low
but consistent daily NSAID used over a period of years such
as ibuprofen (Advil, Motrin) seems to slow the progress of
Alzheimer's. It seems that NSAIDs may affect the onset of
the disease but is of little use for treating it once it has
progressed to early or full-blown Alzheimer's.
It should be noted that some drugs such as acetaminophen,
naproxen, and COX-2 inhibitors, such as celebrex and vioxx,
were found to have no demonstrated benefit (and some
evidence of cardiac harm). This ineffectiveness and the
increase in adverse cardiac events associated with these
agents was reported in various studies in 2004, and
highlights the key role of ibuprofen in the original studies
showing moderated risk associated with NSAID use (PMID
15720180).
A study
(Archives of Neurology 2004; 61:82-88. PMID 14732624) has
reported that the combination of vitamins E and C might,
over time, sharply reduce the risk of Alzheimer's disease.
Marked reduction (up to 80% risk reduction) was achieved
after a period of more than five years, but only if dosage
was 400 IU per day of vitamin E plus 500 mg or more per day
of vitamin C. Lesser amounts, such as those found in
multivitamin pills, appeared markedly less effective. Large
doses of vitamin E without vitamin C had only a mild effect,
while large doses of vitamin C without vitamin E had no
benefit. However in one small study, 2000 IU per day of
vitamin E did appear to delay the progression of early
Alzheimer’s by several months. Other evidence suggests that
vitamin E becomes a damaging pro-oxidant if given in
isolation (without other antioxidants). Vitamin E can be
recharged after absorbing a free radical by another
antioxidant such as vitamin C or Alpha-lipoic acid. Some
studies suggest that a ratio of at least 1000 mg of vitamin
C to 400 IU of vitamin E is ideal. Recent studies suggest
that the most common forms of E sold in supplements, the
dl-alpha or d-alpha tocopherol form, are of little value,
and that the gamma form of vitamin E, or a mixture of all
the tocopherols and tocotrienols that collectively make up
vitamin E from food, provide the most benefit. Vitamin E is
markedly less effective unless taken with oil.
Improved nutritional status of the B vitamin folic acid was
found to reduce Alzheimer's incidence in a study of an order
of nuns, many of whom volunteered to have their mental
status assessed and donated their brains for study after
death. The "Nun's study" also revealed nuns who, in life,
showed little or no dementia, but upon autopsy were found to
have extensive Alzheimer’s plaques. The unimpaired nuns’
brains were free of evidence of stroke, including
micro-strokes. Nuns whose brains revealed both plaques and
stroke damage, however, were severely impaired in
functioning while alive. Thus avoidance of risk factors for
stroke may be a key element in preventing final progression
to being disabled by Alzheimer's dementia. The discovery of
the co-founding role of stroke supports other research
showing that quitting smoking, weight reduction, and
avoidance of diabetes all reduce Alzheimer's risk. Diabetes
greatly increases Alzheimer's risk, and one factor at work
may be that the enzyme charged with removing excess insulin
from the blood, the Insulin Degrading Enzyme (IDE), also has
the responsibility for removing Beta-amyloid plaques from
the brain. Perhaps the excess insulin involved in the
pre-diabetic metabolic syndrome, as well as insulin used to
treat existing diabetes, may demand more IDE than the body
is able to produce, leaving none to remove accumulating beta
amyloid plaques from the brain.
Some evidence suggests that Alzheimer's risk may also be
reduced by inclusion of certain kinds of fish in the weekly
diet. Those that contain Omega-3 fatty acids are thought to
most effective.
The natural chemical curcumin, found at 5% concentration in
the spice turmeric, reduces Alzheimer's incidence in a mouse
model and actually dissolves human senile plaques (beta
amyloid) in the test tube (PMID 15590663). These factors
suggest that inclusion of a bit of turmeric or curry spice
in the diet may provide preventive value. Near 100% curcumin
extract capsules are also available. Curcumin is a powerful
antioxidant and a powerful anti-inflammatory. In India,
where turmeric is commonly consumed in curry spices,
Alzheimer's disease afflicts only approximately 1% of the
elderly, whereas in the U.S. a much larger percentage are
afflicted.
There may be a connection between the cholesterol level
inside the brain cells and the deposition of the toxic
amyloid plaques which make the brain cells die. In addition
to lowering cholesterol, the so-called statins (drugs such
as lovastatin, simvastatin, etc.) may have a beneficial role
in reducing inflammation. However, retrospective studies
into possible protective effects of statin drugs as a means
of preventing or delaying Alzheimer’s have been
inconclusive; no protective effect was found in one large
prospective observational study (Arch Neurol.
2005;62:1047-1051. PMID 16009757).
Prospective studies and well-analyzed retrospective studies
show that smoking increases the risk of developing
Alzheimer's (Biomed Pharmacother. 2004 Mar;58(2):95-9. PMID
14992790). The increased risk may be substantial (J Neurol
Neurosurg Psychiatry 2000;68:622-626 (May). PMID 10766894).
Cigarettes contain many substances in addition to nicotine,
and the increased risks incurred by smokers are not to be
confused with the controversial possible slowing of the
progression of established Alzheimer's disease by
administration of pure medical nicotine.
Nutrition
and Alzheimer's
Some work is
being done to investigate the role of raised levels of
homocysteine, and possible
nutritional prevention or treatment through taking of
foods high in B vitamins and
antioxidants to control the levels of homocysteine.
See:
Seshadri S, Beiser A, Selhub J, et al. Plasma
homocysteine as a risk factor for dementia and Alzheimer's
disease. N Engl J Med. 2002 Feb 14;346(7):476-83.
A deficiency
of
DHA, an omega-3 fatty acid, has also been implicated in
Alzheimer's.[14]
Insulin resistance
has also been associated with Alzheimer's. Remarkably,
genetic epidemiology has revealed that the ApoE4 allele is
found at the highest rates in populations that are current
or recently were hunter-gatherers, and at the lowest rates
in populations that have long been adapted to agriculture.
Some have suggested that the ApoE4 gene only contributes to
Alzheimer's when it is found in conjunction with a
high-carbohydrate diet. [15]
Treatment
There is no
cure, although there are drugs which temporarily reduce
neurotransmitter degradation and alleviate some of the
symptoms of the disease.
Acetylcholinesterase inhibitors
Acetylcholinesterase
(AChE) inhibition was thought to be important because there
is selective loss of forebrain
cholinergic neurons as a result of Alzheimer's. AChE-inhibitors
reduce the rate at which acetylcholine (ACh) is broken down
and hence increase the concentration of ACh in the brain (combatting
the loss of ACh caused by the death of the cholinergin
neurons). Acetylcholinesterase-inhibitors seemed to modestly
moderate symptoms but do not prevent disease progression
including cell death.
Examples include:
-
tacrine
- no longer clinically used
-
donepezil
(marketed as Aricept)
-
galantamine
(marketed as Razadyne, formerly Reminyl)
-
rivastigmine
(marketed as Exelon)
Recently, a controversy has
erupted about cholinesterase inhibitors because a study by
Courtney (2004) in the respected medical journal The Lancet
has suggested they are ineffective. The pharmaceutical
companies, but also many unbiased clinicians, dispute the
findings of the study, based on methodologic grounds.
NMDA antagonists
Recent evidence of the
involvement of glutamatergic neuronal excitotoxicity in the
aetiology of Alzheimer's disease led to the development and
introduction of memantine. Memantine is a novel NMDA
receptor antagonist, and has been shown to be moderately
clinically efficacious. (Areosa et al., 2004)
Vaccine
There are
ongoing tests of an Alzheimer's disease vaccine. This was
based on the idea that if you could train the immune system
to recognize and attack beta-amyloid plaque, the immune
system might reverse deposition of amyloid and thus stop the
disease. Initial results in animals were promising. However,
when the first vaccines were used in humans, brain
inflammation occurred in a small fraction of participants,
and the trials were stopped. Participants in the halted
trials continued to be followed, and some showed lingering
benefits in the form of slower progression of the disease.
Recent studies in mice continue to show promise that an
approach may be found to avoid the inflammation issue. It is
hoped that research will provide a better formulation and
that in the future it can be of use in families with history
of Alzheimer's disease.
Pure Medical Nicotine
One study indicated that
intake of pure medical nicotine might help delay progression
of Alzheimer's disease in carriers, but not non-carriers, of
the ApoE4 gene. The issue of whether medical nicotine intake
may delay Alzheimer's progression among some sub-populations
of patients remains a focus of debate. But no one is
advocating smoking, as distinct from prescription nicotine,
for the treatment or prevention of Alzheimer's. In
prospective studies and well-analyzed retrospective studies,
smoking is shown to increase the risk of developing
Alzheimer's. Biomed Pharmacother. 2004 Mar;58(2):95-9.
Social issues
Alzheimer's is considered to
be a major public health challenge since the median age of
the industrialized world's population is increasing
gradually. For this reason, money spent informing the public
of available effective prevention methods may yield
disproportionate benefits. The role of family
caregivers has also become more prominent, as care in
the familiar surroundings of home may delay onset of some
symptoms and delay or eliminate the need for more
professional and costly levels of care.
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