Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a
chronic neurodegenerative disease that usually starts slowly and
worsens over time. It is the cause of 60% to 70% of cases of
dementia. The most common early symptom is difficulty in
remembering recent events (short-term memory loss). As the disease
advances, symptoms can include problems with language, disorientation
(including easily getting lost), mood swings, loss of motivation, not
managing self care, and behavioural issues. As a person's
condition declines, they often withdraw from family and society.
Gradually, bodily functions are lost, ultimately leading to death.
Although the speed of progression can vary, the average life
expectancy following diagnosis is three to nine years.
The cause of
Alzheimer's disease is poorly understood. About 70% of
the risk is believed to be genetic with many genes usually
involved. Other risk factors include a history of head injuries,
depression, or hypertension. The disease process is associated with
plaques and tangles in the brain. A probable diagnosis is based on
the history of the illness and cognitive testing with medical imaging
and blood tests to rule out other possible causes. Initial symptoms
are often mistaken for normal ageing. Examination of brain tissue
is needed for a definite diagnosis. Mental and physical exercise,
and avoiding obesity may decrease the risk of AD; however, evidence to
support these recommendations is not strong. There are no
medications or supplements that decrease risk.
No treatments stop or reverse its progression, though some may
temporarily improve symptoms. Affected people increasingly rely on
others for assistance, often placing a burden on the caregiver; the
pressures can include social, psychological, physical, and economic
elements. Exercise programmes may be beneficial with respect to
activities of daily living and can potentially improve outcomes.
Treatment of behavioural problems or psychosis due to dementia with
antipsychotics is common, but not usually recommended, as there is
little benefit with an increased risk of early death.
In 2015, there were approximately 29.8 million people worldwide with
AD. It most often begins in people over 65 years of age,
although 4% to 5% of cases are early-onset Alzheimer's which begin
before this. It affects about 6% of people 65 years and older.
In 2015, dementia resulted in about 1.9 million deaths. It was
first described by, and later named after, German psychiatrist and
Alois Alzheimer in 1906. In developed countries, AD is
one of the most financially costly diseases.
1 Signs and symptoms
2.4 Tau hypothesis
2.5 Other hypotheses
3.3 Disease mechanism
10 Society and culture
10.1 Social costs
10.2 Caregiving burden
11 Research directions
11.2 Behavioral prevention
11.3 Possible transmission
11.6 Early diagnosis
13 Further reading
14 External links
Signs and symptoms
Stages of Alzheimer's disease
Effects of ageing on memory but not AD
Forgetting things occasionally
Misplacing items sometimes
Minor short-term memory loss
Not remembering exact details
Early stage Alzheimer's
Not remembering episodes of forgetfulness
Forgets names of family or friends
Changes may only be noticed by close friends or relatives
Some confusion in situations outside the familiar
Middle stage Alzheimer's
Greater difficulty remembering recently learned information
Deepening confusion in many circumstances
Problems with sleep
Trouble knowing where they are
Late stage Alzheimer's
Poor ability to think
Repeats same conversations
More abusive, anxious, or paranoid
The disease course is divided into four stages, with a progressive
pattern of cognitive and functional impairment.
The first symptoms are often mistakenly attributed to ageing or
stress. Detailed neuropsychological testing can reveal mild
cognitive difficulties up to eight years before a person fulfils the
clinical criteria for diagnosis of AD. These early symptoms can
affect the most complex activities of daily living. The most
noticeable deficit is short term memory loss, which shows up as
difficulty in remembering recently learned facts and inability to
acquire new information.
Subtle problems with the executive functions of attentiveness,
planning, flexibility, and abstract thinking, or impairments in
semantic memory (memory of meanings, and concept relationships) can
also be symptomatic of the early stages of AD.
Apathy can be
observed at this stage, and remains the most persistent
neuropsychiatric symptom throughout the course of the disease.
Depressive symptoms, irritability and reduced awareness of subtle
memory difficulties are also common. The preclinical stage of the
disease has also been termed mild cognitive impairment (MCI). This
is often found to be a transitional stage between normal ageing and
dementia. MCI can present with a variety of symptoms, and when memory
loss is the predominant symptom, it is termed "amnestic MCI" and is
frequently seen as a prodromal stage of Alzheimer's disease.
In people with AD, the increasing impairment of learning and memory
eventually leads to a definitive diagnosis. In a small percentage,
difficulties with language, executive functions, perception (agnosia),
or execution of movements (apraxia) are more prominent than memory
problems. AD does not affect all memory capacities equally. Older
memories of the person's life (episodic memory), facts learned
(semantic memory), and implicit memory (the memory of the body on how
to do things, such as using a fork to eat or how to drink from a
glass) are affected to a lesser degree than new facts or
Language problems are mainly characterised by a shrinking vocabulary
and decreased word fluency, leading to a general impoverishment of
oral and written language. In this stage, the person with
Alzheimer's is usually capable of communicating basic ideas
adequately. While performing fine motor tasks such as
writing, drawing or dressing, certain movement coordination and
planning difficulties (apraxia) may be present, but they are commonly
unnoticed. As the disease progresses, people with AD can often
continue to perform many tasks independently, but may need assistance
or supervision with the most cognitively demanding activities.
A photograph of a patient at West Riding Lunatic Asylum with dementia
Progressive deterioration eventually hinders independence, with
subjects being unable to perform most common activities of daily
living. Speech difficulties become evident due to an inability to
recall vocabulary, which leads to frequent incorrect word
substitutions (paraphasias). Reading and writing skills are also
progressively lost. Complex motor sequences become less
coordinated as time passes and AD progresses, so the risk of falling
increases. During this phase, memory problems worsen, and the
person may fail to recognise close relatives. Long-term memory,
which was previously intact, becomes impaired.
Behavioural and neuropsychiatric changes become more prevalent. Common
manifestations are wandering, irritability and labile affect, leading
to crying, outbursts of unpremeditated aggression, or resistance to
Sundowning can also appear. Approximately 30% of
people with AD develop illusionary misidentifications and other
delusional symptoms. Subjects also lose insight of their disease
process and limitations (anosognosia).
Urinary incontinence can
develop. These symptoms create stress for relatives and carers,
which can be reduced by moving the person from home care to other
long-term care facilities.
During the final stages, the patient is completely dependent upon
Language is reduced to simple phrases or even single
words, eventually leading to complete loss of speech. Despite
the loss of verbal language abilities, people can often understand and
return emotional signals. Although aggressiveness can still be
present, extreme apathy and exhaustion are much more common symptoms.
Alzheimer's disease will ultimately not be able to perform
even the simplest tasks independently; muscle mass and mobility
deteriorates to the point where they are bedridden and unable to feed
themselves. The cause of death is usually an external factor, such as
infection of pressure ulcers or pneumonia, not the disease itself.
The cause for most Alzheimer's cases is still mostly unknown except
for 1% to 5% of cases where genetic differences have been
identified. Several competing hypotheses exist trying to
explain the cause of the disease.
The genetic heritability of
Alzheimer's disease (and memory components
thereof), based on reviews of twin and family studies, ranges from 49%
to 79%. Around 0.1% of the cases are familial forms of
autosomal (not sex-linked) dominant inheritance, which have an onset
before age 65. This form of the disease is known as early onset
familial Alzheimer's disease. Most of autosomal dominant familial AD
can be attributed to mutations in one of three genes: those encoding
amyloid precursor protein (APP) and presenilins 1 and 2. Most
mutations in the APP and presenilin genes increase the production of a
small protein called Aβ42, which is the main component of senile
plaques. Some of the mutations merely alter the ratio between
Aβ42 and the other major forms—particularly Aβ40—without
increasing Aβ42 levels.
Most cases of
Alzheimer's disease do not exhibit autosomal-dominant
inheritance and are termed sporadic AD, in which environmental and
genetic differences may act as risk factors. The best known genetic
risk factor is the inheritance of the ε4 allele of the apolipoprotein
E (APOE). Between 40 and 80% of people with AD possess at
least one APOEε4 allele. The APOEε4 allele increases the risk of
the disease by three times in heterozygotes and by 15 times in
homozygotes. Like many human diseases, environmental effects and
genetic modifiers result in incomplete penetrance. For example,
certain Nigerian populations do not show the relationship between dose
of APOEε4 and incidence or age-of-onset for
Alzheimer's disease seen
in other human populations. Early attempts to screen up to 400
candidate genes for association with late-onset sporadic AD (LOAD)
resulted in a low yield. More recent genome-wide association
studies (GWAS) have found 19 areas in genes that appear to affect the
risk. These genes include: CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D,
MEF2C, NME8, PTK2B, SORL1, ZCWPW1, SlC24A4, CLU, PICALM, CR1, BIN1,
MS4A, ABCA7, EPHA1, and CD2AP.
Mutations in the
TREM2 gene have been associated with a 3 to 5 times
higher risk of developing Alzheimer's disease. A suggested
mechanism of action is that when
TREM2 is mutated, white blood cells
in the brain are no longer able to control the amount of beta amyloid
The oldest, on which most currently available drug therapies are
based, is the cholinergic hypothesis, which proposes that AD is
caused by reduced synthesis of the neurotransmitter acetylcholine. The
cholinergic hypothesis has not maintained widespread support, largely
because medications intended to treat acetylcholine deficiency have
not been very effective. Other cholinergic effects have also been
proposed, for example, initiation of large-scale aggregation of
amyloid,[unreliable medical source?] leading to generalised
In 1991, the amyloid hypothesis postulated that extracellular amyloid
beta (Aβ) deposits are the fundamental cause of the disease.
Support for this postulate comes from the location of the gene for the
amyloid precursor protein (APP) on chromosome 21, together with the
fact that people with trisomy 21 (Down Syndrome) who have an extra
gene copy almost universally exhibit at least the earliest symptoms of
AD by 40 years of age. Also, a specific isoform of
apolipoprotein, APOE4, is a major genetic risk factor for AD. While
apolipoproteins enhance the breakdown of beta amyloid, some isoforms
are not very effective at this task (such as APOE4), leading to excess
amyloid buildup in the brain. Further evidence comes from the
finding that transgenic mice that express a mutant form of the human
APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain
pathology with spatial learning deficits.
An experimental vaccine was found to clear the amyloid plaques in
early human trials, but it did not have any significant effect on
dementia. Researchers have been led to suspect non-plaque Aβ
oligomers (aggregates of many monomers) as the primary pathogenic form
of Aβ. These toxic oligomers, also referred to as amyloid-derived
diffusible ligands (ADDLs), bind to a surface receptor on neurons and
change the structure of the synapse, thereby disrupting neuronal
communication. One receptor for
Aβ oligomers may be the prion
protein, the same protein that has been linked to mad cow disease and
the related human condition, Creutzfeldt–Jakob disease, thus
potentially linking the underlying mechanism of these
neurodegenerative disorders with that of Alzheimer's disease.
In 2009, this theory was updated, suggesting that a close relative of
the beta-amyloid protein, and not necessarily the beta-amyloid itself,
may be a major culprit in the disease. The theory holds that an
amyloid-related mechanism that prunes neuronal connections in the
brain in the fast-growth phase of early life may be triggered by
ageing-related processes in later life to cause the neuronal withering
of Alzheimer's disease. N-APP, a fragment of APP from the
peptide's N-terminus, is adjacent to beta-amyloid and is cleaved from
APP by one of the same enzymes. N-APP triggers the self-destruct
pathway by binding to a neuronal receptor called death receptor 6
(DR6, also known as TNFRSF21). DR6 is highly expressed in the
human brain regions most affected by Alzheimer's, so it is possible
that the N-APP/DR6 pathway might be hijacked in the ageing brain to
cause damage. In this model, beta-amyloid plays a complementary role,
by depressing synaptic function.
In early 2017, a trial of verubecestat, which inhibits the
beta-secretase protein responsible for creating beta-amyloid protein
was discontinued as an independent panel found "virtually no chance of
finding a positive clinical effect".
In Alzheimer's disease, changes in tau protein lead to the
disintegration of microtubules in brain cells.
The tau hypothesis proposes that tau protein abnormalities initiate
the disease cascade. In this model, hyperphosphorylated tau begins
to pair with other threads of tau. Eventually, they form
neurofibrillary tangles inside nerve cell bodies. When this
occurs, the microtubules disintegrate, destroying the structure of the
cell's cytoskeleton which collapses the neuron's transport system.
This may result first in malfunctions in biochemical communication
between neurons and later in the death of the cells.
A neurovascular hypothesis has been proposed which states that poor
functioning of the blood–brain barrier may be involved.
The cellular homeostasis of biometals such as ionic copper, iron, and
zinc is disrupted in AD, though it remains unclear whether this is
produced by or causes the changes in proteins. These ions affect and
are affected by tau, APP, and APOE, and their dysregulation may
cause oxidative stress that may contribute to the
pathology. The quality of some of these studies
has been criticised, and the link remains controversial.
The majority of researchers do not support a causal connection with
Smoking is a significant AD risk factor. Systemic markers of the
innate immune system are risk factors for late-onset AD.
There is tentative evidence that exposure to air pollution may be a
contributing factor to the development of Alzheimer's disease.
An infection with Spirochetes (a bacterium) in gum disease may cause
dementia and may be involved in the pathogenesis of Alzheimer's
disease. A fungal infection may also be a factor.
One hypothesis posits that dysfunction of oligodendrocytes and their
associated myelin during aging contributes to axon damage, which then
causes amyloid production and tau hyper-phosphorylation as a side
Retrogenesis is a medical hypothesis about the development and
Alzheimer's disease proposed by Barry Reisberg in the
1980s. The hypothesis is that just as the fetus goes through a
process of neurodevelopment beginning with neurulation and ending with
myelination, the brains of people with AD go through a reverse
neurodegeneration process starting with demyelination and death of
axons (white matter) and ending with the death of grey matter.
Likewise the hypothesis is, that as infants go through states of
cognitive development, people with AD go through the reverse process
of progressive cognitive impairment. Reisberg developed the
caregiving assessment tool known as "FAST" (Functional Assessment
Staging Tool) which he says allows those caring for AD patients to
identify the stages of disease progression and that provides advice
about the kind of care needed at each stage.
Main article: Biochemistry of Alzheimer's disease
Histopathologic image of senile plaques seen in the cerebral cortex of
a person with
Alzheimer's disease of presenile onset. Silver
There is cortical atrophy in Alzheimer's disease, associated with loss
of gyri and sulci in the temporal lobe and parietal lobe, and parts of
the frontal cortex and cingulate gyrus.
Alzheimer's disease is characterised by loss of neurons and synapses
in the cerebral cortex and certain subcortical regions. This loss
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. Degeneration is also present
in brainstem nuclei like the locus coeruleus. Studies using MRI
and PET have documented reductions in the size of specific brain
regions in people with AD as they progressed from mild cognitive
impairment to Alzheimer's disease, and in comparison with similar
images from healthy older adults.
Both amyloid plaques and neurofibrillary tangles are clearly visible
by microscopy in brains of those afflicted by AD. Plaques are
dense, mostly insoluble deposits of beta-amyloid peptide and cellular
material outside and around neurons. Tangles (neurofibrillary tangles)
are aggregates of the microtubule-associated protein tau which has
become hyperphosphorylated and accumulate inside the cells themselves.
Although many older individuals develop some plaques and tangles as a
consequence of ageing, the brains of people with AD have a greater
number of them in specific brain regions such as the temporal
lobe. Lewy bodies are not rare in the brains of people with
Enzymes act on the APP (amyloid precursor protein) and cut it into
fragments. The beta-amyloid fragment is crucial in the formation of
senile plaques in AD.
Alzheimer's disease has been identified as a protein misfolding
disease (proteopathy), caused by plaque accumulation of abnormally
folded amyloid beta protein, and tau protein in the brain. Plaques
are made up of small peptides, 39–43 amino acids in length,
called amyloid beta (Aβ).
Aβ is a fragment from the larger amyloid
precursor protein (APP). APP is a transmembrane protein that
penetrates through the neuron's membrane. APP is critical to neuron
growth, survival, and post-injury repair. In Alzheimer's
disease, gamma secretase and beta secretase act together in a
proteolytic process which causes APP to be divided into smaller
fragments. One of these fragments gives rise to fibrils of
amyloid beta, which then form clumps that deposit outside neurons in
dense formations known as senile plaques.
AD is also considered a tauopathy due to abnormal aggregation of the
tau protein. Every neuron has a cytoskeleton, an internal support
structure partly made up of structures called microtubules. These
microtubules act like tracks, guiding nutrients and molecules from the
body of the cell to the ends of the axon and back. A protein called
tau stabilises the microtubules when phosphorylated, and is therefore
called a microtubule-associated protein. In AD, tau undergoes chemical
changes, becoming hyperphosphorylated; it then begins to pair with
other threads, creating neurofibrillary tangles and disintegrating the
neuron's transport system.
Exactly how disturbances of production and aggregation of the
beta-amyloid peptide give rise to the pathology of AD is not
known. The amyloid hypothesis traditionally points to the
accumulation of beta-amyloid peptides as the central event triggering
neuron degeneration. Accumulation of aggregated amyloid fibrils, which
are believed to be the toxic form of the protein responsible for
disrupting the cell's calcium ion homeostasis, induces programmed cell
death (apoptosis). It is also known that
Aβ selectively builds
up in the mitochondria in the cells of Alzheimer's-affected brains,
and it also inhibits certain enzyme functions and the utilisation of
glucose by neurons.
Various inflammatory processes and cytokines may also have a role in
the pathology of Alzheimer's disease.
Inflammation is a general marker
of tissue damage in any disease, and may be either secondary to tissue
damage in AD or a marker of an immunological response. There is
increasing evidence of a strong interaction between the neurons and
the immunological mechanisms in the brain.
Obesity and systemic
inflammation may interfere with immunological processes which promote
Alterations in the distribution of different neurotrophic factors and
in the expression of their receptors such as the brain-derived
neurotrophic factor (BDNF) have been described in AD.
PET scan of the brain of a person with AD showing a loss of function
in the temporal lobe
Alzheimer's disease is usually diagnosed based on the person's medical
history, history from relatives, and behavioural observations. The
presence of characteristic neurological and neuropsychological
features and the absence of alternative conditions is
supportive. Advanced medical imaging with computed
tomography (CT) or magnetic resonance imaging (MRI), and with
single-photon emission computed tomography (SPECT) or positron
emission tomography (PET) can be used to help exclude other cerebral
pathology or subtypes of dementia. Moreover, it may predict
conversion from prodromal stages (mild cognitive impairment) to
Assessment of intellectual functioning including memory testing can
further characterise the state of the disease. Medical
organisations have created diagnostic criteria to ease and standardise
the diagnostic process for practising physicians. The diagnosis can be
confirmed with very high accuracy post-mortem when brain material is
available and can be examined histologically.
The National Institute of Neurological and Communicative Disorders and
Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders
Association (ADRDA, now known as the Alzheimer's Association)
established the most commonly used NINCDS-ADRDA Alzheimer's Criteria
for diagnosis in 1984, extensively updated in 2007. These
criteria require that the presence of cognitive impairment, and a
suspected dementia syndrome, be confirmed by neuropsychological
testing for a clinical diagnosis of possible or probable AD. A
histopathologic confirmation including a microscopic examination of
brain tissue is required for a definitive diagnosis. Good statistical
reliability and validity have been shown between the diagnostic
criteria and definitive histopathological confirmation. Eight
cognitive domains are most commonly impaired in AD—memory, language,
perceptual skills, attention, constructive abilities, orientation,
problem solving and functional abilities. These domains are equivalent
NINCDS-ADRDA Alzheimer's Criteria
NINCDS-ADRDA Alzheimer's Criteria as listed in the Diagnostic
and Statistical Manual of Mental Disorders (DSM-IV-TR) published by
the American Psychiatric Association.
Neuropsychological screening tests can help in the diagnosis of AD. In
the tests, people are instructed to copy drawings similar to the one
shown in the picture, remember words, read, and subtract serial
Neuropsychological tests such as the mini–mental state examination
(MMSE) are widely used to evaluate the cognitive impairments needed
for diagnosis. More comprehensive test arrays are necessary for high
reliability of results, particularly in the earliest stages of the
Neurological examination in early AD will usually
provide normal results, except for obvious cognitive impairment, which
may not differ from that resulting from other diseases processes,
including other causes of dementia.
Further neurological examinations are crucial in the differential
diagnosis of AD and other diseases. Interviews with family members
are also utilised in the assessment of the disease. Caregivers can
supply important information on the daily living abilities, as well as
on the decrease, over time, of the person's mental function. A
caregiver's viewpoint is particularly important, since a person with
AD is commonly unaware of his own deficits. Many times, families
also have difficulties in the detection of initial dementia symptoms
and may not communicate accurate information to a physician.
Supplemental testing provides extra information on some features of
the disease or is used to rule out other diagnoses. Blood tests can
identify other causes for dementia than AD—causes which may, in
rare cases, be reversible. It is common to perform thyroid
function tests, assess B12, rule out syphilis, rule out metabolic
problems (including tests for kidney function, electrolyte levels and
for diabetes), assess levels of heavy metals (e.g. lead, mercury) and
anaemia. (It is also necessary to rule out delirium).
Psychological tests for depression are employed, since depression can
either be concurrent with AD (see Depression of Alzheimer disease), an
early sign of cognitive impairment, or even the cause.
Due to low accuracy, the C-PIB-PET scan is not recommended to be used
as an early diagnostic tool or for predicting the development of
Alzheimer's disease when people show signs of mild cognitive
impairment (MCI). The use of ¹⁸F-FDG PET scans, as a single
test, to identify people who may develop
Alzheimer's disease is also
not supported by evidence.
Intellectual activities such as playing chess or regular social
interaction have been linked to a reduced risk of AD in
epidemiological studies, although no causal relationship has been
At present, there is no definitive evidence to support that any
particular measure is effective in preventing AD. Global studies
of measures to prevent or delay the onset of AD have often produced
inconsistent results. Epidemiological studies have proposed
relationships between certain modifiable factors, such as diet,
cardiovascular risk, pharmaceutical products, or intellectual
activities among others, and a population's likelihood of developing
AD. Only further research, including clinical trials, will reveal
whether these factors can help to prevent AD.
Although cardiovascular risk factors, such as hypercholesterolaemia,
hypertension, diabetes, and smoking, are associated with a higher risk
of onset and course of AD, statins, which are cholesterol
lowering drugs, have not been effective in preventing or improving the
course of the disease.
Long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs) is
associated with a reduced likelihood of developing AD. Evidence
also supports the notion that NSAIDs can reduce inflammation related
to amyloid plaques. No prevention trial has been completed.
They do not appear to be useful as a treatment. Hormone
replacement therapy in menopause, although previously used, may
increase the risk of dementia.
People who engage in intellectual activities such as reading, playing
board games, completing crossword puzzles, playing musical
instruments, or regular social interaction show a reduced risk for
Alzheimer's disease. This is compatible with the cognitive
reserve theory, which states that some life experiences result in more
efficient neural functioning providing the individual a cognitive
reserve that delays the onset of dementia manifestations.
Education delays the onset of AD syndrome without changing the
duration of the disease. Learning a second language even later in
life seems to delay getting Alzheimer disease. Physical activity
is also associated with a reduced risk of AD. Physical exercise
is associated with decreased rate of dementia. Physical exercise
is also effective in reducing symptom severity in those with
People who eat a healthy, Japanese, or
Mediterranean diet have a lower
risk of AD. A
Mediterranean diet may improve outcomes in those
with the disease. Those who eat a diet high in saturated fats and
simple carbohydrates (mono- and disaccharide) have a higher risk.
The Mediterranean diet's beneficial cardiovascular effect has been
proposed as the mechanism of action.
Conclusions on dietary components have at times been difficult to
ascertain as results have differed between population-based studies
and randomised controlled trials. There is limited evidence that
light to moderate use of alcohol, particularly red wine, is associated
with lower risk of AD. There is tentative evidence that caffeine
may be protective. A number of foods high in flavonoids such as
cocoa, red wine, and tea may decrease the risk of AD.
Reviews on the use of vitamins and minerals have not found enough
consistent evidence to recommend them. This includes vitamin
A, C, the alpha-tocopherol form of vitamin E,
selenium, zinc, and folic acid with or without vitamin
B12. Evidence from a single study indicates that the
alpha-tocopherol form of vitamin E may slow cognitive decline.
Trials examining folic acid (B9) and other B vitamins failed to show
any significant association with cognitive decline. Omega-3 fatty
acid supplements from plants and fish, and dietary docosahexaenoic
acid (DHA), do not appear to benefit people with mild to moderate
Curcumin as of 2010 has not shown benefit in people even though there
is tentative evidence in animals. There is inconsistent and
unconvincing evidence that ginkgo has any positive effect on cognitive
impairment and dementia. As of 2008 there is no concrete evidence
that cannabinoids are effective in improving the symptoms of AD or
dementia; however, some research looks promising.
There is no cure for Alzheimer's disease; available treatments offer
relatively small symptomatic benefit but remain palliative in nature.
Current treatments can be divided into pharmaceutical, psychosocial
Three-dimensional molecular model of donepezil, an
acetylcholinesterase inhibitor used in the treatment of AD symptoms
Molecular structure of memantine, a medication approved for advanced
Five medications are currently used to treat the cognitive problems of
AD: four are acetylcholinesterase inhibitors (tacrine, rivastigmine,
galantamine and donepezil) and the other (memantine) is an NMDA
receptor antagonist. The benefit from their use is small.
No medication has been clearly shown to delay or halt the progression
of the disease.
Reduction in the activity of the cholinergic neurons is a well-known
feature of Alzheimer's disease. Acetylcholinesterase inhibitors
are employed to reduce the rate at which acetylcholine (ACh) is broken
down, thereby increasing the concentration of ACh in the brain and
combating the loss of ACh caused by the death of cholinergic
neurons. There is evidence for the efficacy of these medications
in mild to moderate Alzheimer's disease, and some evidence
for their use in the advanced stage. The use of these drugs in
mild cognitive impairment has not shown any effect in a delay of the
onset of AD. The most common side effects are nausea and
vomiting, both of which are linked to cholinergic excess. These side
effects arise in approximately 10–20% of users, are mild to moderate
in severity, and can be managed by slowly adjusting medication
doses. Less common secondary effects include muscle cramps,
decreased heart rate (bradycardia), decreased appetite and weight, and
increased gastric acid production.
Glutamate is an excitatory neurotransmitter of the nervous system,
although excessive amounts in the brain can lead to cell death through
a process called excitotoxicity which consists of the overstimulation
of glutamate receptors.
Excitotoxicity occurs not only in Alzheimer's
disease, but also in other neurological diseases such as Parkinson's
disease and multiple sclerosis.
Memantine is a noncompetitive
NMDA receptor antagonist
NMDA receptor antagonist first used as an anti-influenza agent. It
acts on the glutamatergic system by blocking NMDA receptors and
inhibiting their overstimulation by glutamate.
been shown to have a small benefit in the treatment of Alzheimer's
disease. Reported adverse events with memantine are infrequent
and mild, including hallucinations, confusion, dizziness, headache and
fatigue. The combination of memantine and donepezil has been
shown to be "of statistically significant but clinically marginal
Atypical antipsychotics are modestly useful in reducing aggression and
psychosis in people with Alzheimer's disease, but their advantages are
offset by serious adverse effects, such as stroke, movement
difficulties or cognitive decline. When used in the long-term,
they have been shown to associate with increased mortality.
Stopping antipsychotic use in this group of people appears to be
Huperzine A while promising, requires further evidence before its use
can be recommended.
Psychosocial interventions are used as an adjunct to pharmaceutical
treatment and can be classified within behaviour-, emotion-,
cognition- or stimulation-oriented approaches. Research on efficacy is
unavailable and rarely specific to AD, focusing instead on dementia in
Behavioural interventions attempt to identify and reduce the
antecedents and consequences of problem behaviours. This approach has
not shown success in improving overall functioning, but can help
to reduce some specific problem behaviours, such as incontinence.
There is a lack of high quality data on the effectiveness of these
techniques in other behaviour problems such as wandering.
Emotion-oriented interventions include reminiscence therapy,
validation therapy, supportive psychotherapy, sensory integration,
also called snoezelen, and simulated presence therapy. A Cochrane
review has found no evidence that this is effective. Supportive
psychotherapy has received little or no formal scientific study, but
some clinicians find it useful in helping mildly impaired people
adjust to their illness.
Reminiscence therapy (RT) involves the
discussion of past experiences individually or in group, many times
with the aid of photographs, household items, music and sound
recordings, or other familiar items from the past. Although there are
few quality studies on the effectiveness of RT, it may be beneficial
for cognition and mood.
Simulated presence therapy (SPT) is based
on attachment theories and involves playing a recording with voices of
the closest relatives of the person with Alzheimer's disease. There is
partial evidence indicating that SPT may reduce challenging
behaviours. Finally, validation therapy is based on acceptance of
the reality and personal truth of another's experience, while sensory
integration is based on exercises aimed to stimulate senses. There is
no evidence to support the usefulness of these therapies.
The aim of cognition-oriented treatments, which include reality
orientation and cognitive retraining, is the reduction of cognitive
deficits. Reality orientation consists in the presentation of
information about time, place or person to ease the understanding of
the person about its surroundings and his or her place in them. On the
other hand, cognitive retraining tries to improve impaired capacities
by exercitation of mental abilities. Both have shown some efficacy
improving cognitive capacities, although in some studies
these effects were transient and negative effects, such as
frustration, have also been reported.
Stimulation-oriented treatments include art, music and pet therapies,
exercise, and any other kind of recreational activities. Stimulation
has modest support for improving behaviour, mood, and, to a lesser
extent, function. Nevertheless, as important as these effects are, the
main support for the use of stimulation therapies is the change in the
Further information: Caregiving and dementia
Since Alzheimer's has no cure and it gradually renders people
incapable of tending for their own needs, caregiving is essentially
the treatment and must be carefully managed over the course of the
During the early and moderate stages, modifications to the living
environment and lifestyle can increase patient safety and reduce
caretaker burden. Examples of such modifications are the
adherence to simplified routines, the placing of safety locks, the
labelling of household items to cue the person with the disease or the
use of modified daily life objects. If eating becomes
problematic, food will need to be prepared in smaller pieces or even
pureed. When swallowing difficulties arise, the use of feeding
tubes may be required. In such cases, the medical efficacy and ethics
of continuing feeding is an important consideration of the caregivers
and family members. The use of physical restraints is rarely
indicated in any stage of the disease, although there are situations
when they are necessary to prevent harm to the person with AD or their
As the disease progresses, different medical issues can appear, such
as oral and dental disease, pressure ulcers, malnutrition, hygiene
problems, or respiratory, skin, or eye infections. Careful management
can prevent them, while professional treatment is needed when they do
arise. During the final stages of the disease, treatment is
centred on relieving discomfort until death, often with the help of
Disability-adjusted life year
Disability-adjusted life year for Alzheimer and other dementias per
100,000 inhabitants in 2004.
The early stages of
Alzheimer's disease are difficult to diagnose. A
definitive diagnosis is usually made once cognitive impairment
compromises daily living activities, although the person may still be
living independently. The symptoms will progress from mild cognitive
problems, such as memory loss through increasing stages of cognitive
and non-cognitive disturbances, eliminating any possibility of
independent living, especially in the late stages of the disease.
Life expectancy of people with AD is less. Following diagnosis it
typically ranges from three to ten years.
Fewer than 3% of people live more than fourteen years. Disease
features significantly associated with reduced survival are an
increased severity of cognitive impairment, decreased functional
level, history of falls, and disturbances in the neurological
examination. Other coincident diseases such as heart problems,
diabetes or history of alcohol abuse are also related with shortened
survival. While the earlier the age at onset the higher
the total survival years, life expectancy is particularly reduced when
compared to the healthy population among those who are younger.
Men have a less favourable survival prognosis than women.
Pneumonia and dehydration are the most frequent immediate causes of
death brought by AD, while cancer is a less frequent cause of death
than in the general population.
Rates after age 65
Two main measures are used in epidemiological studies: incidence and
prevalence. Incidence is the number of new cases per unit of
person–time at risk (usually number of new cases per thousand
person–years); while prevalence is the total number of cases of the
disease in the population at any given time.
Regarding incidence, cohort longitudinal studies (studies where a
disease-free population is followed over the years) provide rates
between 10 and 15 per thousand person–years for all dementias and
5–8 for AD, which means that half of new dementia cases
each year are AD. Advancing age is a primary risk factor for the
disease and incidence rates are not equal for all ages: every five
years after the age of 65, the risk of acquiring the disease
approximately doubles, increasing from 3 to as much as 69 per thousand
person years. There are also sex differences in the
incidence rates, women having a higher risk of developing AD
particularly in the population older than 85. The risk of
Alzheimer's disease is 26% higher among the non-Hispanic
white population than among the non-Hispanic black population, whereas
the Hispanic population has a 30% lower risk than the non-Hispanic
Deaths per million persons in 2012 due to dementias including
Prevalence of AD in populations is dependent upon different factors
including incidence and survival. Since the incidence of AD increases
with age, it is particularly important to include the mean age of the
population of interest. In the United States, Alzheimer prevalence was
estimated to be 1.6% in 2000 both overall and in the 65–74 age
group, with the rate increasing to 19% in the 75–84 group and to 42%
in the greater than 84 group.
Prevalence rates in less developed
regions are lower. The
World Health Organization
World Health Organization estimated that
in 2005, 0.379% of people worldwide had dementia, and that the
prevalence would increase to 0.441% in 2015 and to 0.556% in
2030. Other studies have reached similar conclusions.
Another study estimated that in 2006, 0.40% of the world population
(range 0.17–0.89%; absolute number 26.6 million, range 11.4–59.4
million) were afflicted by AD, and that the prevalence rate would
triple and the absolute number would quadruple by 2050.
See also: Timeline of Alzheimer's disease
Alois Alzheimer's patient
Auguste Deter in 1902. Hers was the first
described case of what became known as Alzheimer's disease.
The ancient Greek and Roman philosophers and physicians associated old
age with increasing dementia. It was not until 1901 that German
Alois Alzheimer identified the first case of what became
known as Alzheimer's disease, named after him, in a fifty-year-old
woman he called Auguste D. He followed her case until she died in
1906, when he first reported publicly on it. During the next five
years, eleven similar cases were reported in the medical literature,
some of them already using the term Alzheimer's disease. The
disease was first described as a distinctive disease by Emil Kraepelin
after suppressing some of the clinical (delusions and hallucinations)
and pathological features (arteriosclerotic changes) contained in the
original report of Auguste D. He included Alzheimer's disease,
also named presenile dementia by Kraepelin, as a subtype of senile
dementia in the eighth edition of his Textbook of Psychiatry,
published on 15 July, 1910.
For most of the 20th century, the diagnosis of
Alzheimer's disease was
reserved for individuals between the ages of 45 and 65 who developed
symptoms of dementia. The terminology changed after 1977 when a
conference on AD concluded that the clinical and pathological
manifestations of presenile and senile dementia were almost identical,
although the authors also added that this did not rule out the
possibility that they had different causes. This eventually led
to the diagnosis of
Alzheimer's disease independent of age. The
term senile dementia of the Alzheimer type (SDAT) was used for a time
to describe the condition in those over 65, with classical Alzheimer's
disease being used to describe those who were younger. Eventually, the
Alzheimer's disease was formally adopted in medical nomenclature
to describe individuals of all ages with a characteristic common
symptom pattern, disease course, and neuropathology.
Society and culture
Alzheimer's disease organisations
Dementia, and specifically Alzheimer's disease, may be among the most
costly diseases for society in
Europe and the United States,
while their costs in other countries such as Argentina, and South
Korea, are also high and rising. These costs will probably
increase with the ageing of society, becoming an important social
problem. AD-associated costs include direct medical costs such as
nursing home care, direct nonmedical costs such as in-home day care,
and indirect costs such as lost productivity of both patient and
caregiver. Numbers vary between studies but dementia costs
worldwide have been calculated around $160 billion, while
Alzheimer's disease in the
United States may be
$100 billion each year.
The greatest origin of costs for society is the long-term care by
health care professionals and particularly institutionalisation, which
corresponds to 2/3 of the total costs for society. The cost of
living at home is also very high, especially when informal costs
for the family, such as caregiving time and caregiver's lost earnings,
are taken into account.
Costs increase with dementia severity and the presence of behavioural
disturbances, and are related to the increased caregiving time
required for the provision of physical care. Therefore, any
treatment that slows cognitive decline, delays institutionalisation or
reduces caregivers' hours will have economic benefits. Economic
evaluations of current treatments have shown positive results.
Further information: Caregiving and dementia
The role of the main caregiver is often taken by the spouse or a close
Alzheimer's disease is known for placing a great burden
on caregivers which includes social, psychological, physical or
Home care is usually preferred by
people with AD and their families. This option also delays or
eliminates the need for more professional and costly levels of
care. Nevertheless, two-thirds of nursing home residents
Dementia caregivers are subject to high rates of physical and mental
disorders. Factors associated with greater psychosocial problems
of the primary caregivers include having an affected person at home,
the carer being a spouse, demanding behaviours of the cared person
such as depression, behavioural disturbances, hallucinations, sleep
problems or walking disruptions and social isolation.
Regarding economic problems, family caregivers often give up time from
work to spend 47 hours per week on average with the person with
AD, while the costs of caring for them are high. Direct and indirect
costs of caring for an Alzheimer's patient average between $18,000 and
$77,500 per year in the United States, depending on the
Cognitive behavioural therapy and the teaching of coping strategies
either individually or in group have demonstrated their efficacy in
improving caregivers' psychological health.
Alzheimer's disease in the media
AD has been portrayed in films such as: Iris (2001), based on John
Bayley's memoir of his wife Iris Murdoch; The Notebook (2004),
based on Nicholas Sparks' 1996 novel of the same name; A Moment
to Remember (2004);
Thanmathra (2005); Memories of Tomorrow
(Ashita no Kioku) (2006), based on Hiroshi Ogiwara's novel of the same
Away from Her
Away from Her (2006), based on Alice Munro's short story
"The Bear Came over the Mountain";
Still Alice (2014), about a
Columbia University professor who has early onset Alzheimer's disease,
based on Lisa Genova's 2007 novel of the same name and featuring
Julianne Moore in the title role. Documentaries on Alzheimer's disease
include Malcolm and Barbara: A Love Story (1999) and Malcolm and
Barbara: Love's Farewell (2007), both featuring Malcolm
Alzheimer's disease research
In the decade 2002–2012, 244 compounds were assessed in Phase I,
Phase II, or Phase III trials, and only one of these (memantine)
FDA approval (though others were still in the pipeline).
Solanezumab failed to show effectiveness in patients who already had
One area of clinical research is focused on treating the underlying
disease pathology. Reduction of beta-amyloid levels is a common target
of compounds (such as apomorphine) under investigation.
Immunotherapy or vaccination for the amyloid protein is one treatment
modality under study. Unlike preventative vaccination, the
putative therapy would be used to treat people already diagnosed. It
is based upon the concept of training the immune system to recognise,
attack, and reverse deposition of amyloid, thereby altering the course
of the disease. An example of such a vaccine under investigation
was ACC-001, although the trials were suspended in
2008. Another similar agent is bapineuzumab, an antibody designed
as identical to the naturally induced anti-amyloid antibody.
However, immunotherapeutic agents have been found to cause some
concerning adverse drug reactions, such as amyloid-related imaging
abnormalities. Other approaches are neuroprotective agents, such
as AL-108, and metal-protein interaction attenuation agents, such
as PBT2. A TNFα receptor-blocking fusion protein, etanercept has
showed encouraging results.
In 2008, two separate clinical trials showed positive results in
modifying the course of disease in mild to moderate AD with
methylthioninium chloride, a drug that inhibits tau
aggregation, and dimebon, an antihistamine. The
consecutive phase-III trial of dimebon failed to show positive effects
in the primary and secondary endpoints. Work with
methylthioninium chloride showed that bioavailability of
methylthioninium from the gut was affected by feeding and by stomach
acidity, leading to unexpectedly variable dosing. A new
stabilised formulation, as the prodrug LMTX, is in phase-III trials
Preliminary research on the effects of meditation on retrieving memory
and cognitive functions have been encouraging.[qualify evidence]
A 2015 review suggests that mindfulness-based interventions may
prevent or delay the onset of mild cognitive impairment and
Rare cases of possible transmission between people are being
studied, e.g. to growth hormone patients.
The herpes simplex virus HSV-1 has been found in the same areas as
amyloid plaques. This suggested the possibility that AD could be
treated or prevented with antiviral medication. Studies of
antivirals in cell cultures have shown promising results.
Fungal infection of AD brain has also been described. This
hypothesis was proposed by the microbiologist L. Carrasco when his
group found statistical correlation between disseminated mycoses and
AD. Further work revealed that fungal infection is present in
different brain regions of AD patients, but not in the control
individuals.  A fungal infection explains the symptoms
observed in AD patients. The slow progression of AD fits with the
chronic nature of some systemic fungal infections, which can be
asymptomatic and thus, unnoticed and untreated. The fungal
hypotheses is also compatible with some other established AD
hypotheses, like the amyloid hypothesis, that can be explained as an
immune system response to an infection in the CNS, as
found by R. Moir and R. Tanzi in mouse and worm models of AD.
Of the many medical imaging techniques available, single photon
emission computed tomography (SPECT) appears to be superior in
Alzheimer's disease from other types of dementia, and
this has been shown to give a greater level of accuracy compared with
mental testing and medical history analysis. Advances have led to
the proposal of new diagnostic criteria.
PiB PET remains investigational, but a similar PET scanning
radiopharmaceutical called florbetapir, containing the longer-lasting
radionuclide fluorine-18, has recently been tested as a diagnostic
tool in Alzheimer's disease, and given
FDA approval for this
Amyloid imaging is likely to be used in conjunction with other markers
rather than as an alternative. Volumetric MRI can detect changes
in the size of brain regions. Measuring those regions that atrophy
during the progress of
Alzheimer's disease is showing promise as a
diagnostic indicator. It may prove less expensive than other imaging
methods currently under study.
In 2011 An
FDA panel voted unanimously to recommend approval of
florbetapir, which is currently used in an investigational study. The
imaging agent can help to detect Alzheimer's brain plaques, but will
require additional clinical research before it can be made available
Emphasis in Alzheimer's research has been placed on diagnosing the
condition before symptoms begin. A number of biochemical tests
have been developed to attempt earlier detection. One such test
involves the analysis of cerebrospinal fluid for beta-amyloid or tau
proteins, both total tau protein and phosphorylated tau181P
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Alzheimer's Disease: Unraveling the Mystery. US Department of Health
and Human Services, National Institute on Aging, NIH. 2008. Archived
from the original on 8 January 2012.
Can Alzheimer's Disease Be Prevented? (PDF). US Department of Health
and Human Services, National Institute on Aging, NIH. 2009. Archived
from the original (PDF) on 2 May 2013.
Caring for a Person with Alzheimer's Disease: Your Easy-to-Use Guide
from the National Institute on Aging. US Department of Health and
Human Services, National Institute on Aging, NIH. 2009. Archived from
the original on 8 January 2012.
Russell D, Barston S, White M (19 December 2007). "Alzheimer's
Behavior Management: Learn to Manage Common Behavior Problems".
helpguide.org. Archived from the original on 23 February 2008.
Retrieved 29 February 2008.
Greater cognitive deterioration in women than men with Alzheimer's
disease: a meta analysis. Journal of Clinical and Experimental
doi:10.1080/13803395.2012.712676. PMID 22913619.
V · T · D
ICD-10: G30, F00
ICD-9-CM: 331.0, 290.1
Patient UK: Alzheimer's disease
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Alzheimer's disease at Curlie (based on DMOZ)
Mental and behavioral disorders (F00–F99 & 290–319)
Mild cognitive impairment
AIDS dementia complex
Organic brain syndrome
Psychoactive substances, substance abuse, drug abuse and
Schizophrenia, schizotypal and delusional
Psychosis and schizophrenia-like disorders
Brief reactive psychosis
Disorganized (hebephrenic) schizophrenia
Folie à deux
(Major depressive disorder
Seasonal affective disorder
Neurotic, stress-related and somatoform
Specific social phobia
Generalized anxiety disorder
(Acute stress reaction
Adjustment disorder with depressed mood
Body dysmorphic disorder
Da Costa's syndrome
Mass psychogenic illness
Dissociative identity disorder
(REM sleep behavior disorder
(Hypoactive sexual desire disorder
(Female sexual arousal disorder)
Adult personality and behavior
Sexual maturation disorder
Ego-dystonic sexual orientation
Sexual relationship disorder
Impulse control disorder
Disorders typically diagnosed in childhood
X-linked intellectual disability
Emotional and behavioral
(Separation anxiety disorder)
Symptoms and uncategorized
Intermittent explosive disorder
Psychogenic non-epileptic seizures
Diseases of the nervous system, primarily CNS (G04–G47, 323–349)
Cavernous sinus thrombosis
Tropical spastic paraparesis
Basal ganglia disease
Primary progressive aphasia
Frontotemporal dementia/Frontotemporal lobar degeneration
Dementia with Lewy bodies
Posterior cortical atrophy
Central pontine myelinolysis
Transient global amnesia
Congenital central hypoventilation syndrome
Circadian rhythm sleep disorder
Advanced sleep phase disorder
Delayed sleep phase disorder
Non-24-hour sleep–wake disorder
Choroid plexus papilloma
Idiopathic intracranial hypertension
Spinal cord compression
Primary lateral sclerosis
Hereditary spastic paraplegia
Distal hereditary motor neuronopathies
Spinal muscular atrophies
Progressive muscular atrophy
Progressive bulbar palsy
Infantile progressive bulbar palsy
Amyotrophic lateral sclerosis
Amyloidosis (E85, 277.3)
Common amyloid forming proteins
AA/Familial Mediterranean fever
Familial amyloid neuropathy
ACys+ABri/Cerebral amyloid angiopathy
Primary cutaneous amyloidosis
ACal/Medullary thyroid cancer