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Alzheimer's disease

2007 Schools Wikipedia Selection. Related subjects: Health and medicine

   CAPTION: Alzheimer's disease
   Classifications and external resources

   Histopathogic image of senile plaques seen in the cerebral cortex in a
   patient with Alzheimer disease of presenile onset. Silver impregnation.
   ICD- 10 G 30., F 00.
   ICD- 9 331.0, 290.1
   OMIM 104300
   DiseasesDB 490
   MedlinePlus 000760
   eMedicine neuro/13

   Alzheimer's disease (AD) is a neurodegenerative disease characterized
   by progressive cognitive deterioration together with declining
   activities of daily living and neuropsychiatric symptoms or behavioural
   changes. It is the most common type of dementia.

   The most striking early symptom is loss of short term memory (
   amnesia), which usually manifests as minor forgetfulness that becomes
   steadily more pronounced with illness progression, with relative
   preservation of older memories. As the disorder progresses, cognitive
   (intellectual) impairment extends to the domains of language (
   aphasia), skilled movements ( apraxia), recognition ( agnosia), and
   those functions (such as decision-making and planning) closely related
   to the frontal and temporal lobes of the brain as they become
   disconnected from the limbic system, reflecting extension of the
   underlying pathological process. These changes make up the essential
   human qualities, and thus AD is sometimes described as a disease where
   the victims suffer the loss of qualities that define human existence.

   This pathological process consists principally of neuronal loss or
   atrophy, principally in the temporoparietal cortex, but also in the
   frontal cortex, together with an inflammatory response to the
   deposition of amyloid plaques and neurofibrillary tangles.

   The ultimate cause of the disease is unknown. Genetic factors are known
   to be important, and dominant mutations in three different genes have
   been identified that account for a much smaller number of cases of
   familial, early-onset AD. For the more common form of late onset AD
   (LOAD), only one susceptibility gene has so far been identified called
   ApoE4.

History

   In 1901, Dr. Alois Alzheimer, a German psychiatrist, interviewed a
   patient named Mrs. Auguste D age 51. He showed her several objects and
   later asked her what she had been shown. She could not remember. He
   would initially record her behaviour as "amnestic writing disorder,"
   but Mrs. Auguste D. would be the first patient to be identified with
   Alzheimer's disease.

   Alzheimer would later work in the laboratory of the esteemed Emil
   Kraepelin in Munich, Germany. Kraepelin was the author of a leading
   textbook in psychiatry and was a strong believer that neuropathology
   could be linked to clinical psychiatric function. Early in April 1906,
   Auguste D died, and Alzheimer worked with two Italian physicians to
   examine her anatomy and neuropathology. On November 3, 1906, he
   presented Auguste D's case to the 37th Assembly of Southwest German
   Psychiatrists and described the neurofibrillary tangles and amyloid
   plaques that would be the hallmark of the disease. Kraepelin would
   later write about this case and others in his Textbook for Students and
   Doctors and index them under Alzheimer's disease. By 1910, the name of
   the disease was well established among the specialist community.

   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 due to the histopathologic process
   discovered by Dr. Alzheimer (see below for description of brain tissue
   changes). During this time senile dementia itself (as a set of
   symptoms) was considered to be a more or less normal outcome of the
   aging process, and thought to be due to age-related brain arterial
   "hardening." In the 1970s and early 1980s, because the symptoms and
   brain pathology were identical for Alzheimer victims older and younger
   than age 65, the name "Alzheimer's disease" began to be used, within
   and outside the medical profession, equally for afflicted individuals
   of all ages, although in this period the term senile dementia of the
   Alzheimer type (SDAT) was often used to distinguish those over 65 who
   did not fit the classical age criterion. Eventually, the term
   Alzheimer's disease was adopted formally in the psychiatric and
   neurological nomenclature to describe individuals of all ages with the
   characteristic common symptom pattern, disease course, and
   neuropathology. The term Alzheimer disease (without the apostrophe and
   s) also continues to be used commonly in the literature.

Clinical features

   The usual first symptom noticed is short term 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 short-term memory, then of familiar and well-known skills or
   objects or persons. Aphasia, disorientation and disinhibition often
   accompany the loss of memory. Alzheimer's disease may also include
   behavioural changes, such as outbursts of violence or excessive
   passivity in people who have no previous history of such behaviour. 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 in some reported cases up to 22 years.

Stages and symptoms

     * Mild — At the early stage of the disease, patients have a tendency
       to become less energetic or spontaneous, though changes in their
       behaviour often goes unnoticed even by the patients' immediate
       family.
     * Moderate — As the disease progresses to the middle stage, the
       patient might still be able to perform tasks independently, but may
       need assistance with more complicated activities.
     * Severe — As the disease progresses from the middle to late stage,
       the patient will undoubtedly not be able to perform even the
       simplest of tasks on their own and will need constant supervision.
       They may even lose the ability to walk or eat without assistance.

Diagnosis

   The diagnosis is made primarily on the basis of history, 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 diagnose Alzheimer's disease
   conclusively pre-mortem. Expert clinicians who specialize in memory
   disorders can now diagnose AD with an accuracy of 85–90%, but a
   definitive diagnosis of Alzheimer's disease must await microscopic
   examination of brain tissue, generally at autopsy. Functional
   neuroimaging studies such as PET and SPECT scans can provide a
   supporting role where dementia is clearly present, but the type of
   dementia is questioned. Recent studies suggest that SPECT neuroimaging
   approaches clinical exam in diagnostic accuracy and may outperform exam
   at differentiating types of dementia (Alzheimer's disease vs. vascular
   dementia). However, Alzheimer's disease remains a primarily clinical
   diagnosis based on the presence of characteristic neurological features
   and the absence of alternative diagnoses, with possible neuroimaging
   assistance.

   Interviews with family members and/or caregivers are extremely
   important in the initial assessment, as the sufferer him/herself may
   tend to minimize his symptomatology or may undergo evaluation at a time
   when his/her symptoms are less apparent, as quotidian fluctuations
   ("good days and bad days") are a fairly common feature. Such interviews
   also provide important information on the affected individual's
   functional abilities, which are a key indicator of the significance of
   the symptoms and the stage of dementia.

   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, visuospatial abilities, and
   other cognitive functions. Results of psychological tests may not
   readily distinguish Alzheimer's disease from 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". In
   addition, a 2004 study by Cervilla and colleagues showed that tests of
   cognitive ability provide useful predictive information up to a decade
   before the onset of dementia. However, when diagnosing individuals with
   a higher level of cognitive ability, in this study those with IQ's of
   120 or more, patients should not be diagnosed from the standard norm
   but from an adjusted high-IQ norm that measured changes against the
   individual's higher ability level.

Pathology

Biochemical characteristics

   Alzheimer's disease has been identified as a protein misfolding disease
   due to the accumulation of abnormally folded amyloid beta protein in
   the brains of AD patients. Amyloid beta, also written Aβ, is a short
   peptide that is an abnormal proteolytic byproduct of the transmembrane
   protein amyloid precursor protein (APP), whose function is unclear but
   thought to be involved in neuronal development. The presenilins are
   components of proteolytic complex involved in APP processing and
   degradation. Although amyloid beta monomers are soluble and harmless,
   they undergo a dramatic conformational change at sufficiently high
   concentration to form a beta sheet-rich tertiary structure that
   aggregates to form amyloid fibrils that deposit outside neurons in
   dense formations known as senile plaques or neuritic plaques, in less
   dense aggregates as diffuse plaques, and sometimes in the walls of
   small blood vessels in the brain in a process called amyloid angiopathy
   or congophilic angiopathy.

   AD is also considered a tauopathy due to abnormal aggregation of the
   tau protein, a microtubule-associated protein expressed in neurons that
   normally acts to stabilize microtubules in the cell cytoskeleton. Like
   most microtubule-associated proteins, tau is normally regulated by
   phosphorylation; however, in AD patients, hyperphosphorylated tau
   accumulated as paired helical filaments that in turn aggregate into
   masses inside nerve cell bodies known as neurofibrillary tangles and as
   dystrophic neurites associated with amyloid plaques.

Neuropathology

   Both amyloid plaques and neurofibrillary tangles are clearly visible by
   microscopy in AD brains. At an anatomical level, AD is characterized by
   gross diffuse atrophy of the brain and loss of neurons, neuronal
   processes and synapses in the cerebral cortex and certain subcortical
   regions. This results in gross atrophy of the affected regions,
   including degeneration in the temporal lobe and parietal lobe, and
   parts of the frontal cortex and cingulate gyrus. Levels of the
   neurotransmitter acetylcholine are reduced. Levels of the
   neurotransmitters serotonin, norepinephrine, and somatostatin are also
   often reduced. Glutamate levels are usually elevated.

Disease mechanism

   Three major competing hypotheses exist to explain the cause of the
   disease. The oldest, on which most currently available drug therapies
   are based, is known as the " cholinergic hypothesis" and suggests that
   AD begins as a deficiency in the production of the neurotransmitter
   acetylcholine. The medications that treat acetylcholine deficiency have
   served to only treat symptoms of the disease and have neither halted
   nor reversed it. The cholinergic hypothesis has not maintained
   widespread support in the face of this evidence, although cholingeric
   effects have been proposed to initiate large-scale aggregation leading
   to generalized neuroinflammation.

   Research after 2000 includes hypotheses centered on the effects of the
   misfolded and aggregated proteins, amyloid beta and tau. The two
   positions are lightheartedly described as "ba-ptist" and "tau-ist"
   viewpoints in scientific publications by Alzheimer's disease
   researchers. "Tau-ists" believe that the tau protein abnormalities
   initiate the disease cascade, while "ba-ptists" believe that beta
   amyloid deposits are the causative factor in the disease. The tau
   hypothesis is supported by the long-standing observation that
   deposition of amyloid plaques do not correlate well with neuron loss;
   however, a majority of researchers support the alternative hypothesis
   that amyloid is the primary causative agent.

   The amyloid hypothesis is initially compelling because the gene for the
   amyloid beta precursor APP is located on chromosome 21, and patients
   with trisomy 21 - better known as Down syndrome - who thus have an
   extra gene copy almost universally exhibit AD-like disorders by 40
   years of age. The traditional formulation of the amyloid hypothesis
   points to the cytotoxicity of mature aggregated amyloid fibrils, which
   are believed to be the toxic form of the protein responsible for
   disrupting the cell's calcium ion homeostasis and thus inducing
   apoptosis. A more recent and widely supported hypothesis suggests that
   the cytotoxic species is an intermediate misfolded form of amyloid
   beta, neither a soluble monomer nor a mature aggregated polymer but an
   oligomeric species. Relevantly, much early development work on lead
   compounds has focused on the inhibition of fibrillization, but the
   toxic-oligomer theory would imply that prevention of oligomeric
   assembly is the more important process or that a better target lies
   upstream, for example in the inhibition of APP processing to amyloid
   beta.

   It should be noted further that ApoE4, the major genetic risk factor
   for AD, leads to excess amyloid build up in the brain before AD
   symptoms arise. Thus, beta-amyloid deposition precedes clinical AD.
   Another strong support for the amyloid hypothesis, which looks at the
   beta-amyloid as the common initiating factor for the Alzheimer's
   disease, is that transgenic mice solely expressing a mutant human APP
   gene develop first diffuse and then fibrillar beta-amyloid plaques,
   associated with neuronal and microglial damage.

   And yet another support for the amyloid hypothesis comes from the
   knowledge of other amyloid diseases. Humans get many amyloid diseases,
   generally referred to as amyloidosis. Blocking the production of the
   responsible amyloid protein ( e.g., beta-amyloid in AD) can
   successfully treat these diseases .

Genetics

   Rare cases of Alzheimer's 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 Alzheimer's disease (FAD). Evidence from rodent
   studies suggests that the FAD mutation of PS1 results in impaired
   hippocampal-dependent learning which is correlated with reduced adult
   neurogenesis in the dentate gyrus. Mutations in the APP gene on
   chromosome 21 can also cause early onset disease. The presenilins have
   been identified as essential components of the proteolytic processing
   machinery that produces beta amyloid peptides through cleavage of APP.

   Most cases identified are "sporadic" with no clear family history.
   Environmental factors sometimes claimed to increase risk of Alzheimer's
   include prior head injury, particularly repeated trauma, previous
   incidents of migraine headaches, exposure to defoliants, and low
   activity levels during adulthood.

   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). Researchers are
   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, the beta
   secretase enzymes insulin-degrading enzyme endothelin-converting
   enzymes and inflammatory 5-lipoxygenase gene.

Genetic linkage

   Alzheimer's disease is definitely linked to the 1st, 14th, and 21st
   chromosomes, but other linkages are controversial and not, as yet,
   confirmed. While some genes predisposing to AD have been identified ,
   such as ApoE4 on chromosome 19, sporadic AD also involves other risk
   and protective genes still awaiting confirmation.

Epidemiology and prevention

   Alzheimer's disease is the most frequent type of dementia in the
   elderly and affects almost half of all patients with dementia.
   Correspondingly, advancing age is the primary risk factor for
   Alzheimer's. Among people aged 65, 2-3% show signs of the disease,
   while 25 - 50% of people 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. Every five years after the
   age of 65, the probability of having the disease doubles. The share of
   Alzheimer's patients over the age of 85 is the fastest growing segment
   of the Alzheimer's disease population in the US, although current
   estimates suggest the 75-84 population has about the same number of
   patients as the over 85 population.

   The evidence relating certain behaviors, dietary intakes, environmental
   exposures, and diseases to the likelihood of developing Alzhemier's
   varies in quality and its acceptance by the medical community. It is
   important to understand that interventions that reduce the risk of
   developing disease in the first place may not alter disease progression
   after symptoms become apparent. Due to their observational design,
   studies examining disease risk factors are often at risk from
   confounding variables. Several recent large, randomized controlled
   trials—in particular the Women's Health Initiative—have called into
   question preventive mesasures based on cross-sectional studies. Some
   proposed preventive measures are even based on studies conducted solely
   in animals.

Risk reducers

     * Intellectual stimulation (e.g., playing chess or doing a crossword)
     * Regular physical exercise
     * Regular social interaction
     * A generally healthy diet low in saturated fat, supplemented in
       particular with:
          + B vitamins
          + Omega-3 fatty acids, especially Docosahexaenoic acid
          + Fruit and vegetable juice
          + High doses of the antioxidant Vitamin E (in combination with
            vitamin C) seem to reduce Alzheimer's risk in cross sectional
            studies but not in a randomized trial and so are not currently
            a recommended preventive measure because of observed increases
            in overall mortality
     * Cholesterol-lowering drugs ( statins) reduce Alzheimer's risk in
       observational studies but so far not in randomized controlled
       trials
     * Hormone replacement therapy is no longer thought to prevent
       dementia based on data from the Women's Health Initiative
     * Regular use of non-steroidal anti-inflammatory drugs like ibuprofen
       and aspirin reduces the chance of dementia but the risks appear to
       outweigh the drugs' benefit as a method of primary prevention

Risk factors

     * Advancing age
     * ApoE epsilon 4 genotype (in some populations)
     * Head injury
     * Poor cardiovascular health (including smoking, diabetes,
       hypertension, high cholesterol)
     * Exposure to light metals is a proposed but not widely-accepted risk
       factor. Aluminium, a neurotoxin, is often present in higher
       quantities in brains of Alzheimers patients, but no causal
       relationship has yet been found. Copper is another candidate.

Treatment

   There is currently no cure for Alzheimer's disease. Currently available
   medications offer relatively small symptomatic benefit for some
   patients but do not slow disease progression. The American Association
   for Geriatric Psychiatry published a consensus statement on Alzheimer's
   treatment in 2006.

Acetylcholinesterase inhibitors

   Acetylcholinesterase (AChE) inhibition was thought to be important
   because there is a reduction in activity of the cholinergic neurons.
   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 alter the course of the underlying dementing
   process.

   Examples include:
     * tacrine - no longer clinically used
     * donepezil - (marketed as Aricept)
     * galantamine - (marketed as Razadyne in the U.S.A. Marketed as
       Reminyl or Nivalin in the rest of the world)
     * rivastigmine - (marketed as Exelon)

   There is significant doubt as to the effectiveness of cholinesterase
   inhibitors. A number of recent articles have criticized the design of
   studies reporting benefit from these drugs, concluding that they have
   doubtful clinical utility, are costly, and confer many side effects.
   The pharmaceutical companies, but also some independent clinicians,
   dispute the conclusions of these articles. A transdermal patch is under
   development that may ease administration of rivastigmine.

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.

Psychosocial interventions

   Cognitive and behavioral interventions and rehabilitation strategies
   may be used as an adjunct to pharmacologic treatment, especially in the
   early to moderately advanced stages of disease. Treatment modalities
   include counseling, psychotherapy (if cognitive functioning is
   adequate), reminiscent therapy, reality orientation therapy, and
   behavioural reinforcements as well as cognitive rehabilitation
   training.

Treatments in clinical development

   A large number of potential treatments for Alzheimer's disease are
   currently under investigation, including four compounds being studied
   in phase 3 clinical trials. Xaliproden had been shown to reduce
   neurodegeneration in animal studies. Tramiprosate (3APS or Alzhemed) is
   a GAG-mimetic molecule that is believed to act by binding to soluble
   amyloid beta to prevent the accumulation of the toxic plaques.
   R-flurbiprofen (MPC-7869) is a gamma secretase modulator sometimes
   called a selective amyloid beta 42 lowering agent. It is believed to
   reduce the production of the toxic amyloid beta in favour of shorter
   forms of the peptide. Leuprolide is has also been studied for
   Alzheimer’s. It is hypothesized to work by reducing leutenizing hormone
   levels which may be causing damage in the brain as one ages.
     * Vaccines or immunotherapy for Alzheimer's, unlike typical vaccines,
       would be used to treat diagnosed patients rather than for disease
       prevention. Ongoing efforts are based on the idea that, by training
       the immune system to recognize and attack beta-amyloid, the immune
       system might reverse deposition of amyloid and thus stop the
       disease. Initial results using this approach in animals were
       promising, and human-trials of drug AN-1792 showed results in 20%
       of patients; however, 6% of multi-dosed participants (18 of 300)
       developed encephalitis in 2002, and the trials were stopped.
       Participants in the halted trials continued to be followed, and 20%
       "developed high levels of antibodies to beta-amyloid" and some
       showed slower progression of the disease, maintaining memory-test
       levels while placebo-patients worsened. Work is continuing on less
       toxic Aβ vaccines, such as a DNA-based therapy that recently showed
       promise in mice.

     * Proposed alternative treatments for Alzheimer's include a range of
       herbal compounds and dietary supplements. In general, research on
       the efficacy of these substances is either non-existent or far too
       weak to support therapeutic claims of improved memory or slowed
       disease progression.

   In the AAGP review from 2006, Vitamin E in doses below 400 IU was
   mentioned as having conflicting evidence in efficacy to prevent AD.
   Higher doses were discouraged as these may be linked with higher
   mortality related to cardiac events. Ginkgo biloba did not show enough
   long-term efficacy to recommend its use, but it is being studied in a
   large randomized clinical study in the US.

   Laboratory studies with cells and animals continually fuel the pipeline
   of potential treatments. Some currently approved drugs such as statins
   and thiazolidinediones have also been under investigation for the
   treatment and prevention of Alzheimer’s. Recent clinical trials for
   Phase 2 and Phase 3 in this category have taken 12 to 18 months under
   study drug, plus additional months for patient enrollment and analysis.
   Compounds that are just entering into human trials or are in
   pre-clinical trials would be at least 4 years from being available to
   the public and would be available only if they can demonstrate safety
   and efficacy in human trials.

Occupational and lifestyle therapies

   Modifications to the living environment and lifestyle of the
   Alzheimer's patient can improve functional performance and ease
   caretaker burden. Assessment by an occupational therapist is often
   indicated. Adherence to simplified routines and labeling of household
   items to cue the patient can aid with activities of daily living, while
   placing safety locks on cabinets, doors, and gates and securing
   hazardous chemicals and guns can prevent accidents and wandering.
   Changes in routine or environment can trigger or exacerbate agitiation,
   whereas well-lit rooms, adquate rest, and avoidance of excess
   stimulation all help prevent such episodes. Appropriate social and
   visual stimulation, however, can improve function by increasing
   awareness and orientation. For instance, boldly colored tableware aids
   those with severe AD, helping people overcome a diminished sensitivity
   to visual contrast to increase food and beverage intake.

Social issues

   Alzheimer's is a major public health challenge since the median age of
   the industrialized world's population is increasing gradually. 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. 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. However, home-based care may entail tremendous economic,
   emotional, and even psychological costs as well. Family caregivers
   often give up time from work and foregoing pay to spend 47 hours per
   week on average with an affected loved one who frequently cannot be
   left alone. From a survey of patients with long term care insurance,
   direct and indirect costs of caring for an Alzheimer's patient average
   $77,500 per year.

Statistics on Alzheimer's disease

     * In the USA, AD was the 7th leading cause of death in 2004, with
       65,829 number of deaths (and rising).
     * At over $100 billion per year, AD is the third most costly disease
       in the U.S., after heart disease and cancer.
     * There are an estimated 24 million people with dementia worldwide.
     * By 2040, it is projected that this figure will have increased to 81
       million.
     * An estimated 4.5 million Americans have Alzheimer’s disease.
     * It is projected that 14.3 million Americans will have the disease
       by mid-century: a 350 percent increase from 2000.
     * The federal government estimates spending approximately $647
       million for Alzheimer’s disease research in fiscal year 2005.
     * The average lifetime cost of care for an individual with
       Alzheimer’s is $174,000.

Notable cases

   Notable cases of Alzheimer's disease have included President Ronald
   Reagan, Charlton Heston, Ralph Waldo Emerson, and Rita Hayworth. For a
   more comprehensive list, see List of famous Alzheimer's disease
   sufferers.

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