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Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, self-neglect, and behavioral 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 typical life expectancy following diagnosis is three to nine years.
The cause of Alzheimer's disease is poorly understood. There are many environmental and genetic risk factors associated with its development. The strongest genetic risk factor is from an allele of APOE. Other risk factors include a history of head injury, clinical depression, and high blood pressure. The disease process is largely associated with amyloid plaques, neurofibrillary tangles, and loss of neuronal connections 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 aging. Examination of brain tissue is needed for a definite diagnosis, but this can only take place after death. Good nutrition, physical activity, and engaging socially
are known to be of benefit generally in aging, and these may help in
reducing the risk of cognitive decline and Alzheimer's; in 2019 clinical
trials were underway to look at these possibilities. There are no medications or supplements that have been shown to 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 programs may be beneficial with respect to activities of daily living and can potentially improve outcomes. Behavioral problems or psychosis due to dementia are often treated with antipsychotics, but this is not usually recommended, as there is little benefit and an increased risk of early death.
As of 2015, there were approximately 29.8 million people worldwide with AD with about 50 million of all forms of dementia as of 2020. It most often begins in people over 65 years of age, although up to 10 per cent of cases are early-onset affecting those in their 30's to mid 60's. Women get sick more often than men. It affects about 6% of people 65 years and older. In 2015, all forms of dementia resulted in about 1.9 million deaths. The disease is named after German psychiatrist and pathologist Alois Alzheimer, who first described it in 1906. Alzheimer's financial burden on society is large, on par with the costs of cancer and heart disease, costing 200 billion dollars in the US alone.
Signs and symptoms
The course of Alzheimer's is generally described in three stages, with a progressive pattern of cognitive and functional impairment. The three stages are described as early or mild, middle or moderate, and late or severe. The disease is known to target the hippocampus which is associated with memory,
and this is responsible for the first symptoms of memory impairment. As
the disease progresses so does the degree of memory impairment.
First symptoms
The first symptoms are often mistakenly attributed to aging or stress. Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of Alzheimer's disease. 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 Alzheimer's disease. Apathy
and depression can be seen at this stage, with apathy remaining as the
most persistent symptom throughout the course of the disease. 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 aging 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. Amnestic MCI has a greater than 90% likelihood of being associated with Alzheimer's.
Early stage
In people with Alzheimer's disease, 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. Alzheimer's disease 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 memories.
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 Alzheimer's disease can often
continue to perform many tasks independently, but may need assistance or
supervision with the most cognitively demanding activities.
Middle stage
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
Alzheimer's disease 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.
Behavioral and neuropsychiatric changes become more prevalent. Common manifestations are wandering, irritability and emotional lability, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Sundowning can also appear. Approximately 30% of people with Alzheimer's disease 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.
Late stage
A normal brain on the left and a late-stage Alzheimer's brain on the right.
During the final stage, known as the late-stage or severe stage, the patient is completely dependent upon caregivers. 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. People with 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.
Causes
Alzheimer's disease is believed to occur when abnormal amounts of amyloid beta, accumulating extracellularly as amyloid plaques, and tau proteins, accumulating intracellularly as neurofibrillary tangles, form in the brain affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function. This altered protein clearance ability is age-related, regulated by brain cholesterol, and associated with other neurodegenerative diseases.
The cause for most Alzheimer's cases is still mostly unknown
except for 1-2% of cases where deterministic genetic differences have
been identified. Several competing hypotheses exist trying to explain the cause of the disease.
Genetic
Only 1–2% of Alzheimer's cases are inherited (autosomal dominant). These types are known as early onset familial Alzheimer's disease, can have a very early onset, and a faster rate of progression. Early onset familial Alzheimer's disease can be attributed to mutations in one of three genes: those encoding amyloid-beta precursor protein (APP) and presenilins PSEN1 and PSEN2. Most mutations in the APP and presenilin genes increase the production of a small protein called amyloid beta (Aβ)42, which is the main component of amyloid plaques.
Some of the mutations merely alter the ratio between Aβ42 and the other
major forms—particularly Aβ40—without increasing Aβ42 levels. Two other genes associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1.
Most cases of Alzheimer's are not inherited and are termed
sporadic Alzheimer's disease, in which environmental and genetic
differences may act as risk factors.
Most cases of sporadic Alzheimer's disease in contrast to familial
Alzheimer's disease are late-onset Alzheimer's disease (LOAD) developing
after the age of 65 years. Less than 5% of sporadic Alzheimer's disease
have an earlier onset. The strongest genetic risk factor for sporadic Alzheimer's disease is APOEε4. APOEε4 is one of four alleles of apolipoprotein E
(APOE). APOE plays a major role in lipid-binding proteins in
lipoprotein particles and the epsilon4 allele disrupts this function. Between 40 and 80% of people with Alzheimer's disease 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 Alzheimer's disease (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.
Alleles 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 in some variants in TREM2,
white blood cells in the brain are no longer able to control the amount
of amyloid beta present. Many single-nucleotide polymorphisms
(SNPs) are associated with Alzheimer's, with a 2018 study adding 30
SNPs by differentiating Alzheimer's disease into six categories,
including memory, language, visuospatial, and executive functioning.
Osaka mutation
A Japanese pedigree of familial Alzheimer's disease was found to be associated with a deletion mutation of codon 693 of APP. This mutation and its association with Alzheimer's disease was first reported in 2008,
and is known as the Osaka mutation. Only homozygotes with this mutation
develop Alzheimer's disease. This mutation accelerates Aβ
oligomerization but the proteins do not form the amyloid fibrils that
aggregate into amyloid plaques, suggesting that it is the Aβ
oligomerization rather than the fibrils that may be the cause of this
disease. Mice expressing this mutation have all the usual pathologies of
Alzheimer's disease.
Cholinergic hypothesis
The oldest hypothesis, on which most drug therapies are based, is the cholinergic hypothesis, which proposes that Alzheimer's disease 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.
Amyloid hypothesis
The 1991 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 Alzheimer's disease by 40 years of age. Also, a specific isoform of apolipoprotein, APOE4,
is a major genetic risk factor for Alzheimer's disease. 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.
Tau hypothesis
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 as paired helical filaments. 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.
Inflammatory hypothesis
A number of studies connect the misfolded amyloid beta and tau
proteins associated with the pathology of Alzheimer's disease, as
bringing about oxidative stress that leads to chronic inflammation.
Sustained inflammation (neuroinflammation) is also a feature of other
neurodegenerative diseases including Parkinson's disease, and ALS. Spirochete infections have also been linked to dementia.
Sleep disturbances
are seen as a possible risk factor for inflammation in Alzheimer's
disease. Sleep problems have been seen as a consequence of Alzheimer's
disease but studies suggest that they may instead be a causal factor.
Sleep disturbances are thought to be linked to persistent inflammation. A possible role of chronic periodontal infection and the gut microbiota has been suggested.
Other hypotheses
Cholesterol signaling
hypothesis postulates that amyloid production and tau phosphorylation
are regulated by cholesterol and high brain cholesterol contributes to
the disease. First, the cholesterol is made in the astrocytes, the
astrocytes load the cholesterol into the cholesterol carrier protein apoE,
and the apoE loads the cholesterol into the neurons. Once in the
neurons, cholesterol causes clustering of amyloid precursor protein
(APP) with its hydrolytic enzyme gamma secretase, resulting in amyloid
beta production and accumulation of amyloid plaques. Cholesterol regulates amyloid beta production by substrate presentation.
A neurovascular hypothesis stating that poor functioning of the blood–brain barrier may be involved has been proposed.
The cellular homeostasis of biometals
such as ionic copper, iron, and zinc is disrupted in Alzheimer's
disease, 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 aluminium.
Smoking is a significant Alzheimer's disease risk factor. Systemic markers of the innate immune system are risk factors for late-onset Alzheimer's disease.
There is tentative evidence that exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.
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 effect.
Retrogenesis is a medical hypothesis about the development and progress of 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 Alzheimer's disease 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 Alzheimer's disease 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 people with Alzheimer's disease to identify the stages of disease
progression and that provides advice about the kind of care needed at
each stage.
The association with celiac disease
is unclear, with a 2019 study finding no increase in dementia overall
in those with CD, while a 2018 review found an association with several
types of dementia including Alzheimer's disease.
Kynurenines are a downstream metabolite of tryptophan
and have the potential to be neuroactive. This may be associated with
the neuropsychiatric symptoms and cognitive prognosis in mild dementia. A
five-year study focused on the role of kynurenine in Alzheimer's and
Lewy body disease and found its increase to be associated with more
hallucinations.
Pathophysiology
Neuropathology
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 particularly the locus coeruleus in the pons. Studies using MRI and PET
have documented reductions in the size of specific brain regions in
people with Alzheimer's disease as they progressed from mild cognitive
impairment to Alzheimer's disease, and in comparison with similar images
from healthy older adults.
Both Aβ plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by Alzheimer's disease, especially in the hippocampus. However, Alzheimer's disease may occur without neurofibrillary tangles in the neocortex. 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 aging, the brains of people with Alzheimer's disease 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 Alzheimer's disease.
Biochemistry
Enzymes
act on the APP (amyloid-beta precursor protein) and cut it into
fragments. The beta-amyloid fragment is crucial in the formation of
amyloid plaques in Alzheimer's disease.
Alzheimer's disease has been identified as a protein misfolding disease, a proteopathy, caused by the accumulation of abnormally folded amyloid beta protein into amyloid plaques, and tau protein into neurofibrillary tangles in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called amyloid beta (Aβ). Amyloid beta is a fragment from the larger amyloid-beta precursor protein (APP) a transmembrane protein that penetrates 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 amyloid plaques.
Alzheimer's disease 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 Alzheimer's disease, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system. Pathogenic tau can also cause neuronal death through transposable element dysregulation.
Disease mechanism
Exactly how disturbances of production and aggregation of the
beta-amyloid peptide give rise to the pathology of Alzheimer's disease
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
Alzheimer's disease 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 disease progression.
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 Alzheimer's disease.
Diagnosis
PET scan of the brain of a person with Alzheimer's disease 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 behavioral 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 Alzheimer's disease. Approved radiopharmaceutical diagnostic agents used in PET for patients with Alzheimer's disease: florbetapir (2012), flutemetamol (2013), florbetaben (2014), flortaucipir (2020).
Assessment of intellectual functioning including memory testing can further characterise the state of the disease.
Medical organizations 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.
Criteria
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 Alzheimer's disease. 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 intellectual domains are most commonly impaired in AD—memory, language, perceptual skills, attention, motor skills, orientation, problem solving and executive functional abilities. These domains are equivalent to the 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.
Techniques
Cognitive tests such as the
Mini–Mental State Examination
(MMSE) can help in the diagnosis of Alzheimer's disease. In this test
instructions are given to copy drawings like the one shown, remember
some words, read, and subtract numbers serially.
Neuropsychological tests including cognitive 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
disease. Neurological examination
in early Alzheimer's disease 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 Alzheimer's disease 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 Alzheimer's disease is commonly unaware of their 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 Alzheimer's 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.
Prevention
Intellectual activities such as playing
chess
or regular social interaction have been linked to a reduced risk of
Alzheimer's disease in epidemiological studies, although no causal
relationship has been found.
There is no evidence that supports any particular measure as being effective in preventing Alzheimer's disease.
Global studies of measures to prevent or delay the onset of Alzheimer's
disease 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 Alzheimer's disease. Only further research, including
clinical trials, will reveal whether these factors can help to prevent
Alzheimer's disease.
Medication
Cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and worsened course of Alzheimer's disease. Blood pressure medications may decrease the risk. A review found that the use of statins, which lower cholesterol may be of benefit in Alzheimer's and other dementias but not in vascular dementia.
Long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs) were thought in 2007 to be associated with a reduced likelihood of developing Alzheimer's disease. Evidence also suggested the notion that NSAIDs could reduce inflammation related to amyloid plaques, but trials were suspended due to high adverse events. No prevention trial has been completed. They do not appear to be useful as a treatment, but as of 2011 were thought to be candidates as presymptomatic preventives. Hormone replacement therapy in menopause, although previously used, may increase risk of dementia.
Lifestyle
Evidence suggests that higher education and occupational attainment,
and participation in leisure activities show a reduced risk of
developing Alzheimer's, or of delaying the onset of symptoms. 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 Alzheimer's disease syndrome without changing the duration of the disease. Learning a second language even later in life seems to delay the onset of Alzheimer's disease.
Physical exercise is associated with decreased rate of dementia. Physical exercise is also effective in reducing symptom severity in those with Alzheimer's disease.
Diet
Diet is seen to be a modifiable risk factor for the development of dementia. The Mediterranean diet, and the DASH diet
are both associated with less cognitive decline. A different approach
has been to incorporate elements of both of these diets into one known
as the MIND diet.
These diets are generally low in saturated fats while providing a good
source of carbohydrates, mainly those that help stabilize blood sugar
and insulin levels. Those who eat a diet high in saturated fats and simple carbohydrates (mono- and disaccharide) have a higher risk.
Raised blood sugar levels over a long time, can damage nerves and cause memory problems if they are not managed. Nutritional factors associated with the proposed diets for reducing dementia risk, include unsaturated fatty acids, antioxidants vitamin E, vitamin C, and flavonoids, vitamin B, and vitamin D. The MIND diet may be more protective but further studies are
needed. The Mediterranean diet seems to be more protective against
Alzheimer's than DASH but there are no consistent findings against
dementia in general. The role of olive oil needs further study as it may be one of the most important components in reducing the risk of cognitive decline and dementia.
In those with celiac disease or non-celiac gluten sensitivity, a strict gluten-free diet may relieve the symptoms given a mild cognitive impairment. Once dementia is advanced no evidence suggests that a gluten free diet is useful Conclusions on dietary components have 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 Alzheimer's disease. 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 Alzheimer's disease. A number of studies have looked at the possible role of minerals such as selenium, zinc, and copper. Omega 3 fatty acid supplements from plants and fish, and dietary docosahexaenoic acid (DHA), do not appear to benefit people with mild to moderate Alzheimer's disease.
Curcumin as of 2010 had not shown benefit in people even though there is tentative evidence in animals. There is growing evidence (2020) for the neuroprotection offered by the use of cannabinoids
in Alzheimer's and other neurodegenerative disorders. However, further
population studies are recommended to see this use beyond experimental.
Management
There is no cure for Alzheimer's disease; available treatments offer relatively small symptomatic benefits but remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial, and caregiving.
Medications
Molecular structure of
memantine, a medication approved for advanced Alzheimer's disease symptoms
Medications used to treat the cognitive problems of Alzheimer's disease include: four acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine, and donepezil) and memantine, an NMDA receptor antagonist. The benefit from their use is small.
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, 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 Alzheimer's disease. 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 first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate. Memantine has been shown to have a small benefit in the treatment of moderate to severe 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 effectiveness".
An extract of Ginkgo biloba known as EGb 761 has been widely used for treating Alzheimer's and other neuropsychiatric disorders. Its use is approved throughout Europe.
The World Federation of Biological Psychiatry guidelines lists EGb 761
with the same weight of evidence (level B) given to acetylcholinesterase
inhibitors, and memantine. EGb 761 is the only one that showed
improvement of symptoms in both Alzheimer's disease and vascular
dementia. EGb 761 is seen as being able to play an important role either
on its own or as an add-on particularly when other therapies prove
ineffective.
EGb 761 is seen to be neuroprotective; it is a free radical scavenger,
improves mitochondrial function, and modulates serotonin and dopamine
levels. Many studies of its use in mild to moderate dementia have shown
it to significantly improve cognitive function, activities of daily
living, and neuropsychiatric symptoms. However, its use has not been
shown to prevent the progression to dementia.
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 safe.
Psychosocial intervention
Psychosocial
interventions are used as an adjunct to pharmaceutical treatment and
can be classified within behavior-, emotion-, cognition- or
stimulation-oriented approaches. Research on efficacy is unavailable and
rarely specific to Alzheimer's disease, focusing instead on dementia in
general.
Behavioral interventions
attempt to identify and reduce the antecedents and consequences of
problem behaviors. This approach has not shown success in improving
overall functioning, but can help to reduce some specific problem behaviors, such as incontinence. There is a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering. Music therapy is effective in reducing behavioral and psychological symptoms.
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. A 2018 review of the effectiveness of RT found that
effects were inconsistent, small in size and of doubtful clinical
significance, and varied by setting. 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 behaviors.
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 of 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 exercising 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 behavior, 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 person's routine.
Caregiving
Since Alzheimer's has no cure and it gradually renders people
incapable of tending to their own needs, caregiving is essentially the
treatment and must be carefully managed over the course of the disease.
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 labeling 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 puréed. 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 Alzheimer's disease or their caregivers.
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 hospice.
Prognosis
Disability-adjusted life year for Alzheimer and other dementias per 100,000 inhabitants in 2004.
No data
≤ 50
50–70
70–90
90–110
110–130
130–150
150–170
170–190
190–210
210–230
230–250
≥ 250
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 Alzheimer's disease is reduced. The normal life expectancy for 60 to 70 years old is 23 to 15 years; for 90 years old it is 4.5 years.
Following Alzheimer's disease diagnosis it ranges from 7 to 10 years
for those in their 60s and early 70s (a loss of 13 to 8 years), to only
about 3 years or less (a loss of 1.5 years) for those in their 90s. It is about 50% life expectancy with Alzheimer's disease.
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 Alzheimer's disease, while cancer is a less frequent cause of death than in the general population.
Epidemiology
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.
Deaths per million persons in 2012 due to dementias including Alzheimer's disease
0–4
5–8
9–10
11–13
14–17
18–24
25–45
46–114
115–375
376–1266
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 Alzheimer's disease,
which means that half of new dementia cases each year are Alzheimer's
disease. 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 Alzheimer's disease particularly in the
population older than 85. In the United States,
the risk of dying from 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 white population.
The prevalence of Alzheimer's disease in populations is dependent
upon different factors including incidence and survival. Since the
incidence of Alzheimer's disease increases with age, it is particularly
important to include the mean age of the population of interest. In the
United States, Alzheimer's 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 groups. Prevalence rates in less developed regions are lower. The 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 Alzheimer's disease, and that the prevalence rate
would triple and the absolute number would quadruple by 2050.
History
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 psychiatrist 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 Alzheimer's disease 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 term 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
Social costs
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 aging 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 costs of 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 behavioral 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.
Caregiving burden
The role of the main caregiver is often taken by the spouse or a close relative. Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical or economic aspects. Home care is usually preferred by people with Alzheimer's disease 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 have dementias.
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 behaviors of the cared person such as depression,
behavioral 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
Alzheimer's disease, while the costs of caring for them are high. Direct
and indirect costs of caring for somebody with Alzheimer's average
between $18,000 and $77,500 per year in the United States, depending on
the study.
Cognitive behavioral therapy and the teaching of coping strategies either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.
Media
Alzheimer's disease 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 name; 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 Pointon. It has also been portrayed in music by English musician the Caretaker in releases such as Persistent Repetition of Phrases (2008), An Empty Bliss Beyond This World (2011), and Everywhere at the End of Time (2016–2019). Paintings depicting the disorder include the late works by American artist William Utermohlen, who drew self-portraits from 1995 to 2000 as an experiment of showing his disease through art.
Research directions
Treatment and prevention
In the decade 2002–2012, 244 compounds were assessed in Phase I, Phase II, or Phase III trials, and only one of these (memantine) received FDA approval (though others were still in the pipeline). Solanezumab and aducanumab failed to show effectiveness in people who already had Alzheimer's symptoms.
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 2018 and 2019, more trials, including aducanumab which reduced amyloid beta concentrations, failed, leading some to question the validity of the amyloid hypothesis.
The senescence-accelerated mouse (SAMP8) is an Alzheimer's
disease (AD) animal model in which amyloid precursor protein (APP) is
overproduced. The mice develop early memory disturbances and alterations
in the blood-brain barrier, which causes a decreased expulsion of
amyloid-β protein from the brain. It has a marked increase in oxidative
stress in the brain. Medications that reduce oxidative stress have been
shown to improve memory. Treatments that reduce amyloid-β (antisense to
APP and antibodies to amyloid-β) not only improve memory but also reduce
oxidative stress. It has been shown that the initial deviations in
lipid peroxidative damage favor mitochondrial dysfunction as being a
trigger for amyloid-β overproduction in this Alzheimer's disease mouse
strain. This process begets increased amyloid-beta, which further
damages mitochondria.
Research on the effects of meditation on preserving memory and cognitive functions is at an early stage. A 2015 review suggests that mindfulness-based interventions may prevent or delay the onset of mild cognitive impairment and Alzheimer's disease.
The ketogenic diet is a very high-fat, adequate-protein, low-carbohydrate diet
that is used to treat refractory epilepsy in children. Designed to
mimic some of the effects of fasting, following a ketogenic diet leads
to elevated blood levels of molecules called ketone bodies: a metabolic state known as ketosis.
These ketone bodies have a neuroprotective effect on aging brain cells,
though it is not fully understood why. Limited research in the form of
preclinical trials (mice and rats), and small-scale clinical (human)
trials, have explored its potential as a therapy for neurodegenerative
disorders like Alzheimer's disease.
Infections
The herpes simplex virus HSV-1 has been found in the same areas as amyloid plaques. This suggested the possibility that Alzheimer's disease could be treated or prevented with antiviral medication. Studies of antivirals in cell cultures have shown promising results.
A 2021 study of 265,172 subjects in Sweden over a 12-year period found
that patients with herpes diagnoses not treated with antiviral drugs had
a 50% increased risk of dementia over controls, but treatment with
antiviral drugs reduced the incidence by 25%.
Fungal infection of Alzheimer's disease brain has also been described.
This hypothesis was proposed by the microbiologist L. Carrasco when his group found statistical correlation between disseminated mycoses and Alzheimer's disease.
Further work revealed that fungal infection is present in different
brain regions of Alzheimer's disease patients, but not in the control
individuals.
A fungal infection explains the symptoms observed in Alzheimer's
disease patients. The slow progression of Alzheimer's disease fits with
the chronic nature of some systemic fungal infections, which can be
asymptomatic and thus, unnoticed and untreated.
The fungal hypotheses are also compatible with some other established
Alzheimer's disease 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 Alzheimer's disease.
Diagnosis
Emphasis in Alzheimer's research has been placed on diagnosing the condition before symptoms begin. A number of biochemical tests have been developed to enable earlier detection. Some such tests involve the analysis of cerebrospinal fluid for beta-amyloid, total tau protein and phosphorylated tau181P protein concentrations.
Because drawing CSF can be painful, repeated draws are avoided. A blood
test for circulatory miRNA and inflammatory biomarkers is a potential
alternative indicator.
A series of studies suggest that aging-related breakdown of the
blood–brain barrier may be causative of Alzheimer's disease, and
conclude that markers for that damage may be an early predictor of the
disease.
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