Alzheimer's disease (AD), also known in medical literature as Alzheimer disease, is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death. It was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. Most often, AD is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier. In 2006, there were 26.6 million people worldwide with AD. Alzheimer's is predicted to affect 1 in 85 people globally by 2050.
Although Alzheimer's disease develops differently for every individual, there are many common symptoms. Early symptoms are often mistakenly thought to be 'age-related' concerns, or manifestations of stress. In the early stages, the most common symptom is difficulty in remembering recent events, known as short term memory loss. When AD is suspected, the diagnosis is usually confirmed with tests that evaluate behaviour and thinking abilities, often followed by a brain scan if available, however, examination of brain tissue is required for a definitive diagnosis. As the disease advances, symptoms can include confusion, irritability, aggression, mood swings, trouble with language, and long-term memory loss. As the person's condition declines they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Since the disease is different for each individual, predicting how it will affect the person is difficult. AD develops for an unknown and variable amount of time before becoming fully apparent, and it can progress undiagnosed for years. On average, the life expectancy following diagnosis is approximately seven years. Fewer than 3% of individuals live more than 14 years after diagnosis.
AD is classified as a neurodegenerative disorder. The cause and progression of the disease are not well understood; it is associated with plaques and tangles in the brain. Current treatments only help with the symptoms of the disease. There are no available treatments that stop or reverse the progression of the disease. As of 2012[update], more than 1,000 clinical trials have been or are being conducted to test various compounds in AD.Mental stimulation, exercise, and a balanced diet have been suggested as ways to delay cognitive symptoms (though not brain pathology) in healthy older individuals, but there is no conclusive evidence supporting an effect.
Because AD cannot be cured and is degenerative, the affected person increasingly relies on others for assistance. 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; the pressures can be wide-ranging, involving social, psychological, physical, and economic elements of the caregiver's life. In developed countries, AD is one of the most costly diseases to society.
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 daily living activities. The most noticeable deficit is 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 also occur commonly. The preclinical stage of the disease has also been termed mild cognitive impairment, but whether this term corresponds to a different diagnostic stage or identifies the first step of AD is a matter of dispute.
In people with AD the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small portion of them, 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) are affected to a lesser degree than new facts or memories.
Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, which lead 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 co-ordination 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.
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.
During the final stage of AD, the person 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. Persons with Alzheimer's disease will ultimately not be able to perform even the simplest tasks without any assistance.Muscle mass and mobility deteriorate to the point where they are bedridden, and they lose the ability to feed themselves. AD is a terminal illness, with the cause of death typically being 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:
Around 0.1% of the cases are familial forms of autosomal (not sex-linked) dominant inheritance, which usually 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—e.g., Aβ40—without increasing Aβ42 levels. This suggests that presenilin mutations can cause disease even if they lower the total amount of Aβ produced and may point to other roles of presenilin or a role for alterations in the function of APP and/or its fragments other than Aβ. There exist variants of the APP gene which are protective.
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, 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 present.
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 neurotransmitteracetylcholine. 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, leading to generalised neuroinflammation.
In 1991, the amyloid hypothesis postulated that extracellular beta-amyloid (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 AD by 40 years of age. Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. Whilst 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 Aβoligomers (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 Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.
The tau hypothesis is the idea 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, collapsing the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.
Herpes simplex virus type 1 has been proposed to play a causative role in people carrying the susceptible versions of the apoE gene.
The cellular homeostasis of 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. Some studies have shown an increased risk of developing AD with environmental factors such as the intake of metals, particularly aluminium. The quality of some of these studies has been criticised, and other studies have concluded that there is no relationship between these environmental factors and the development of AD. Some have hypothesized that dietary copper may play a causal role.
Another hypothesis asserts that the disease may be caused by age-related myelin breakdown in the brain. Iron released during myelin breakdown is hypothesised to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as beta-amyloid and tau.
AD individuals show 70% loss of locus coeruleus cells that provide norepinephrine (in addition to its neurotransmitter role) that locally diffuses from "varicosities" as an endogenous anti-inflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus. It has been shown that norepinephrine stimulates mouse microglia to suppress Aβ-induced production of cytokines and their phagocytosis of Aβ. This suggests that degeneration of the locus ceruleus might be responsible for increased Aβ deposition in AD brains.
There is tentative evidence that exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.
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-amyloidpeptide 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 AD.
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.
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 gives 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 calciumionhomeostasis, 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.
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.
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 numbers.
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 disease.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. (See differential diagnosis for Dementia). (It is also necessary to rule out delirium).
Emphasis in Alzheimer's research has been placed on diagnosing the condition before symptoms begin. A number of biochemical tests have been developed to allow for early detection. One such test involves the analysis of cerebrospinal fluid for beta-amyloid or tau proteins, both total tau protein and phosphorylated tau181P protein concentrations. Searching for these proteins using a spinal tap can predict the onset of Alzheimer's with a sensitivity of between 94% and 100%. When used in conjunction with existing neuroimaging techniques, doctors can identify people with significant memory loss who are already developing the disease.
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 found.
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.
Long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced likelihood of developing AD. Human postmortem studies, in animal models, or in vitro investigations also support the notion that NSAIDs can reduce inflammation related to amyloid plaques. However, trials investigating their use as palliative treatment have failed to show positive results, apparently because the brain NSAID concentration after an oral NSAID dose is exceedingly small. No prevention trial has been completed.Hormone replacement therapy, 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, but is not related to earlier death after diagnosis. 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.
People who eat a mediterranean diet have a lower risk of AD, and it may improve outcomes in those with the disease. Those who eat a diet high in saturated fats and simple carbohydrates have a higher risk. The mediterranean diet's beneficial cardiovascular effect has been proposed as the mechanism of action. 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, E,selenium,zinc, and folic acid with or without vitamin B12. Additionally vitamin E is associated with health risks. Trials examining folic acid (B9) and other B vitamins failed to show any significant association with cognitive decline. In those already affected with AD adding docosahexaenoic acid, an Omega 3 fatty acid, to the diet has not been found to slow decline.
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. Some research in its early stages however 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 and caregiving.
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. Only donepezil is approved for treatment of advanced AD dementia. 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 and are mild to moderate in severity. Less common secondary effects include muscle cramps, decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid production.
Antipsychotic drugs are modestly useful in reducing aggression and psychosis in Alzheimer's disease with behavioural problems, but are associated with serious adverse effects, such as stroke, movement difficulties or cognitive decline, that do not permit their routine use. When used in the long-term, they have been shown to associate with increased mortality.
Huperzine A while promising, requires further evidence before it use can be recommended.
A specifically designed room for sensory integration therapy, also called snoezelen; an emotion-oriented psychosocial intervention for people with dementia
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 general.
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. 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 person's routine.
Since Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs, caregiving essentially is 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 labelling of household items to cue the person with the disease or the use of modified daily life objects. Patients may also become incapable of feeding themselves, so they require food in smaller pieces or 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 caregivers.
A small recent study in the US concluded that people whose caregivers had a realistic understanding of the prognosis and clinical complications of late dementia were less likely to receive aggressive treatment near the end of life. 
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 the population with the disease is reduced. The mean life expectancy following diagnosis is approximately seven 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.
The disease is the underlying cause of death in 70% of all cases.Pneumonia and dehydration are the most frequent immediate causes of death, while cancer is a less frequent cause of death than in the general population.
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, cohortlongitudinal 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 dying from Alzheimer’s disease is twenty-six percent higher among the non-Hispanic white population than among the non-Hispanic black population, whereas the Hispanic population has a thirty percent lower risk than the non-Hispanic white population.
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 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.
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 Romanphilosophers and physicians associated old age with increasing dementia. It was not until 1901 that German psychiatristAlois Alzheimer identified the first case of what became known as Alzheimer's disease 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 preseniledementia 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 independently 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 for those 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
Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for society in Europe and the United States, while their cost in other countries such as Argentina, or South Korea, is 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 nursinghome 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.
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.
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 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 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 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 study.
As of 2012[update], the safety and efficacy of more than 400 pharmaceutical treatments had been or were being investigated in 1012 clinical trials worldwide, and approximately a quarter of these compounds are in Phase III trials, the last step prior to review by regulatory agencies.
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. Other approaches are neuroprotective agents, such as AL-108, and metal-protein interaction attenuation agents, such as PBT2. A TNFα receptor fusion protein, etanercept has showed encouraging results.
The common herpes simplex virus HSV-1 has been found to colocate with amyloid plaques. This suggested the possibility that AD could be treated or prevented with antiviral medication.
Preliminary research on the effects of meditation on retrieving memory and cognitive functions have been encouraging. Limitations of this research can be addressed in future studies with more detailed analyses.
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 commercially.
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 use.
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.
^ abcdefgWaldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B. Recommendations for the Diagnosis and Management of Alzheimer's Disease and Other Disorders Associated with Dementia: EFNS Guideline. European Journal of Neurology. 2007;14(1):e1–26. doi:10.1111/j.1468-1331.2006.01605.x. PMID 17222085.
^Tabert MH, Liu X, Doty RL, Serby M, Zamora D, Pelton GH, Marder K, Albers MW, Stern Y, Devanand DP. A 10-Item Smell Identification Scale Related to Risk for Alzheimer's Disease. Annals of Neurology. 2005;58(1):155–160. doi:10.1002/ana.20533. PMID 15984022.
^ abcdBonin-Guillaume S, Zekry D, Giacobini E, Gold G, Michel JP. Impact économique de la démence (English: The Economical Impact of Dementia). Presse Médicale. 2005;34(1):35–41. French. PMID 15685097.
^Nygård L. Instrumental Activities of Daily Living: A Stepping-stone Towards Alzheimer's Disease Diagnosis in Subjects with Mild Cognitive Impairment?. Acta Neurologica Scandinavica. 2003;Suppl(179):42–6. doi:10.1034/j.1600-0404.107.s179.8.x. PMID 12603250.
^Carlesimo GA, Oscar-Berman M. Memory Deficits in Alzheimer's Patients: A Comprehensive Review. Neuropsychology Review. 1992;3(2):119–69. doi:10.1007/BF01108841. PMID 1300219.
^Jelicic M, Bonebakker AE, Bonke B. Implicit Memory Performance of Patients with Alzheimer's Disease: A Brief Review. International Psychogeriatrics. 1995;7(3):385–392. doi:10.1017/S1041610295002134. PMID 8821346.
^ abTaler V, Phillips NA. Language Performance in Alzheimer's Disease and Mild Cognitive Impairment: a comparative review. Journal of Clinical and Experimental Neuropsychology. July 2008;30(5):501–56. doi:10.1080/13803390701550128. PMID 18569251.
^ abcFrank EM. Effect of Alzheimer's Disease on Communication Function. Journal of the South Carolina Medical Association. 1994;90(9):417–23. PMID 7967534.
^Volicer L, Harper DG, Manning BC, Goldstein R, Satlin A. Sundowning and Circadian Rhythms in Alzheimer's Disease. The American Journal of Psychiatry. 2001 [Retrieved 27 August 2008];158(5):704–11. doi:10.1176/appi.ajp.158.5.704. PMID 11329390.
^Gold DP, Reis MF, Markiewicz D, Andres D. When Home Caregiving Ends: A Longitudinal Study of Outcomes for Caregivers of Relatives with Dementia. Journal of the American Geriatrics Society. 1995;43(1):10–6. PMID 7806732.
^ abSelkoe DJ. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature. 1999;399(6738 Suppl):A23–31. doi:10.1038/19866. PMID 10392577.
^Shioi J, Georgakopoulos A, Mehta P, Kouchi Z, Litterst CM, Baki L, Robakis NK. FAD mutants unable to increase neurotoxic Aβ 42 suggest that mutation effects on neurodegeneration may be independent of effects on Abeta. Journal of Neurochemistry. 2007;101(3):674–81. doi:10.1111/j.1471-4159.2006.04391.x. PMID 17254019.
^Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jönsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.. Nature. 2 August 2012;488(7409):96–9. doi:10.1038/nature11283. PMID 22801501.
^Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J. TREM2 variants in Alzheimer's disease. The New England Journal of Medicine. 2012;368(2):117–27. doi:10.1056/NEJMoa1211851. PMID 23150934.
^Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinistö L, Halonen P, Kontula K. Apolipoprotein E, Dementia, and Cortical Deposition of Beta-amyloid Protein. The New England Journal of Medicine. 1995;333(19):1242–47. doi:10.1056/NEJM199511093331902. PMID 7566000.
Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F. Alzheimer-type Neuropathology in Transgenic Mice Overexpressing V717F Beta-amyloid Precursor Protein. Nature. 1995;373(6514):523–27. doi:10.1038/373523a0. PMID 7845465.
Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D. Comparison of Neurodegenerative Pathology in Transgenic Mice Overexpressing V717F Beta-amyloid Precursor Protein and Alzheimer's Disease. The Journal of Neuroscience. 1996;16(18):5795–811. PMID 8795633.
Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G. Correlative Memory Deficits, Abeta Elevation, and Amyloid Plaques in Transgenic Mice. Science. 1996;274(5284):99–102. doi:10.1126/science.274.5284.99. PMID 8810256.
Lalonde R, Dumont M, Staufenbiel M, Sturchler-Pierrat C, Strazielle C. Spatial Learning, Exploration, Anxiety, and Motor Coordination in Female APP23 Transgenic Mice with the Swedish Mutation. Brain Research. 2002;956(1):36–44. doi:10.1016/S0006-8993(02)03476-5. PMID 12426044.
^Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term Effects of Abeta42 Immunisation in Alzheimer's Disease: Follow-up of a Randomised, Placebo-controlled Phase I Trial. Lancet. 2008;372(9634):216–23. doi:10.1016/S0140-6736(08)61075-2. PMID 18640458.
^Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL. Aß Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease. The Journal of Neuroscience. 2007;27(4):796–807. doi:10.1523/JNEUROSCI.3501-06.2007. PMID 17251419.
^Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I. Tau Pathology in Alzheimer Disease and Other Tauopathies. Biochimica Et Biophysica Acta. 2005;1739(2–3):198–210. doi:10.1016/j.bbadis.2004.09.008. PMID 15615638.
^Chun W, Johnson GV. The Role of Tau Phosphorylation and Cleavage in Neuronal Cell Death. Frontiers in Bioscience: A Journal and Virtual Library. 2007;12:733–56. doi:10.2741/2097. PMID 17127334.
^Rondeau V. A Review of Epidemiologic Studies on Aluminum and Silica in Relation to Alzheimer's Disease and Associated Disorders. Reviews on Environmental Health. 2002;17(2):107–21. doi:10.1515/REVEH.2002.17.2.107. PMID 12222737.
^Brewer GJ. Copper excess, zinc deficiency, and cognition loss in Alzheimer's disease. BioFactors (Oxford, England). March 2012;38(2):107–113. doi:10.1002/biof.1005. PMID 22438177.
^Kheifets L, Bowman JD, Checkoway H, Feychting M, Harrington JM, Kavet R, Marsh G, Mezei G, Renew DC, van Wijngaarden E. Future needs of occupational epidemiology of extremely low frequency electric and magnetic fields: review and recommendations. Occupational and Environmental Medicine. February 2009;66(2):72–80. doi:10.1136/oem.2007.037994. PMID 18805878.
^Eikelenboom P, van Exel E, Hoozemans JJ, Veerhuis R, Rozemuller AJ, van Gool WA. Neuroinflammation – An Early Event in Both the History and Pathogenesis of Alzheimer's Disease. Neuro-Degenerative Diseases. 2010;7(1–3):38–41. doi:10.1159/000283480. PMID 20160456.
^Bartzokis G, Lu PH, Mintz J. Quantifying Age-Related Myelin Breakdown with MRI: Novel Therapeutic Targets for Preventing Cognitive Decline and Alzheimer's Disease. Journal of Alzheimer's Disease. December 2004;6(6 Suppl):S53–9. PMID 15665415.
^Kastenholz B, Garfin DE, Horst J, Nagel KA. Plant Metal Chaperones: A Novel Perspective in Dementia Therapy. Amyloid: The International Journal of Experimental and Clinical Investigation: The Official Journal of the International Society of Amyloidosis. 2009;16(2):81–3. doi:10.1080/13506120902879392. PMID 20536399.
^Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH. Regional Distribution of Neurofibrillary Tangles and Senile Plaques in the Cerebral Cortex of Elderly Patients: A Quantitative Evaluation of a One-year Autopsy Population from a Geriatric Hospital. Cerebral Cortex. 1994;4(2):138–50. doi:10.1093/cercor/4.2.138. PMID 8038565.
^Hashimoto M, Rockenstein E, Crews L, Masliah E. Role of Protein Aggregation in Mitochondrial Dysfunction and Neurodegeneration in Alzheimer's and Parkinson's Diseases. Neuromolecular Medicine. 2003;4(1–2):21–36. doi:10.1385/NMM:4:1-2:21. PMID 14528050.
^Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. Synapse Formation and Function is Modulated by the Amyloid Precursor Protein. The Journal of Neuroscience. 2006;26(27):7212–21. doi:10.1523/JNEUROSCI.1450-06.2006. PMID 16822978.
^Turner PR, O'Connor K, Tate WP, Abraham WC. Roles of Amyloid Precursor Protein and its Fragments in Regulating Neural Activity, Plasticity and Memory. Progress in Neurobiology. 2003;70(1):1–32. doi:10.1016/S0301-0082(03)00089-3. PMID 12927332.
^Hooper NM. Roles of Proteolysis and Lipid Rafts in the Processing of the Amyloid Precursor Protein and Prion Protein. Biochemical Society Transactions. 2005;33(Pt 2):335–8. doi:10.1042/BST0330335. PMID 15787600.
^Van Broeck B, Van Broeckhoven C, Kumar-Singh S. Current Insights into Molecular Mechanisms of Alzheimer Disease and Their Implications for Therapeutic Approaches. Neuro-Degenerative Diseases. 2007;4(5):349–65. doi:10.1159/000105156. PMID 17622778.
^Huang Y, Mucke L. Alzheimer Mechanisms and Therapeutic strategies. Cell. 2012;148(6):1204-22. PMID 22424230.
^Yankner BA, Duffy LK, Kirschner DA. Neurotrophic and Neurotoxic Effects of Amyloid Beta Protein: Reversal by Tachykinin Neuropeptides. Science. 1990;250(4978):279–82. doi:10.1126/science.2218531. PMID 2218531.
^Greig NH, Mattson MP, Perry T, Chan SL, Giordano T, Sambamurti K, Rogers JT, Ovadia H, Lahiri DK. New Therapeutic Strategies and Drug Candidates for Neurodegenerative Diseases: p53 and TNF-alpha Inhibitors, and GLP-1 Receptor Agonists. Annals of the New York Academy of Sciences. 2004;1035:290–315. doi:10.1196/annals.1332.018. PMID 15681814.
^ abMcKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical Diagnosis of Alzheimer's Disease: Report of the NINCDS-ADRDA Work Group under the Auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34(7):939–44. PMID 6610841.
^ abDubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O'brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research Criteria for the Diagnosis of Alzheimer's Disease: Revising the NINCDS-ADRDA Criteria. Lancet Neurology. 2007;6(8):734–46. doi:10.1016/S1474-4422(07)70178-3. PMID 17616482.
^Blacker D, Albert MS, Bassett SS, Go RC, Harrell LE, Folstein MF. Reliability and validity of NINCDS-ADRDA criteria for Alzheimer's disease. The National Institute of Mental Health Genetics Initiative. Archives of Neurology. 1994;51(12):1198–204. PMID 7986174.
^American Psychiatric Association (2000). Diagnostic and statistical manual of mental disorders: DSM-IV-TR (4th Edition Text Revision ed.). Washington, DC: American Psychiatric Association. ISBN0-89042-025-4.
^Ito N. [Clinical aspects of dementia]. [Hokkaido Igaku Zasshi] the Hokkaido Journal of Medical Science. 1996;71(3):315–20. Japanese. PMID 8752526.
^Tombaugh TN, McIntyre NJ. The mini-mental state examination: a comprehensive review. Journal of the American Geriatrics Society. 1992;40(9):922–35. PMID 1512391.
^Marksteiner J, Hinterhuber H, Humpel C. Cerebrospinal Fluid Biomarkers for Diagnosis of Alzheimer's Disease: Beta-amyloid(1–42), Tau, Phospho-tau-181 and Total Protein. Drugs of Today. 2007;43(6):423–31. doi:10.1358/dot.2007.43.6.1067341. PMID 17612711.
^ abParadise M, Cooper C, Livingston G. Systematic Review of the Effect of Education on Survival in Alzheimer's Disease. International Psychogeriatrics. 2009;21(1):25–32. doi:10.1017/S1041610208008053. PMID 19026089.
^Sofi F, Macchi C, Abbate R, Gensini GF, Casini A. Effectiveness of the Mediterranean diet: can it help delay or prevent Alzheimer's disease?. Journal of Alzheimer's Disease. 2010;20(3):795–801. doi:10.3233/JAD-2010-1418. PMID 20182044.
^ abSolfrizzi V, Capurso C, D'Introno A, Colacicco AM, Santamato A, Ranieri M, Fiore P, Capurso A, Panza F. Lifestyle-related Factors in Predementia and Dementia Syndromes. Expert Review of Neurotherapeutics. 2008;8(1):133–58. doi:10.1586/1473718.104.22.168. PMID 18088206.
^Solfrizzi V, Panza F, Frisardi V, Seripa D, Logroscino G, Imbimbo BP, Pilotto A. Diet and Alzheimer's disease risk factors or prevention: the current evidence.. Expert Review of Neurotherapeutics. May 2011;11(5):677–708. doi:10.1586/ern.11.56. PMID 21539488.
^Panza F, Capurso C, D'Introno A, Colacicco AM, Frisardi V, Lorusso M, Santamato A, Seripa D, Pilotto A, Scafato E, Vendemiale G, Capurso A, Solfrizzi V. Alcohol Drinking, Cognitive Functions in Older Age, Predementia, and Dementia Syndromes. Journal of Alzheimer's Disease. May 2009;17(1):7–31. doi:10.3233/JAD-2009-1009. PMID 19494429.
^Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N. Caffeine intake and dementia: systematic review and meta-analysis. Journal of Alzheimer's Disease. 2010;20 Suppl 1:S187–204. doi:10.3233/JAD-2010-091387. PMID 20182026.
^Lerner AJ, Gustaw-Rothenberg K, Smyth S, Casadesus G. Retinoids for treatment of Alzheimer's disease.. BioFactors (Oxford, England). Mar–Apr 2012;38(2):84–9. doi:10.1002/biof.196. PMID 22419567.
^Heo JH, Lee KM. The possible role of antioxidant vitamin C in Alzheimer's disease treatment and prevention. American Journal of Alzheimer's Disease and Other Dementias. March 2013;28(2):120–5. doi:10.1177/1533317512473193. PMID 23307795.
^Malouf R, Grimley Evans J. Folic Acid with or without Vitamin B12 for the Prevention and Treatment of Healthy Elderly and Demented people. The Cochrane Database of Systematic Reviews. 2008;(4):CD004514. doi:10.1002/14651858.CD004514.pub2. PMID 18843658.
^Wald DS, Kasturiratne A, Simmonds M. Effect of Folic Acid, with or without other B vitamins, on Cognitive Decline: Meta-analysis of Randomized trials. The American Journal of Medicine. June 2010;123(6):522–527.e2. doi:10.1016/j.amjmed.2010.01.017. PMID 20569758.
^Cunnane SC, Chouinard-Watkins R, Castellano CA, Barberger-Gateau P. Docosahexaenoic acid homeostasis, brain aging and Alzheimer's disease: Can we reconcile the evidence?. Prostaglandins, Leukotrienes, and Essential Fatty Acids. January 2013;88(1):61–70. doi:10.1016/j.plefa.2012.04.006. PMID 22575581.
^Commission de la transparence. Médicaments de la maladie d'Alzheimer [Drugs for Alzheimer's disease: best avoided. No therapeutic advantage]. Prescrire International. June 2012;21(128):150. PMID 22822592.
^Stahl SM. The new cholinesterase inhibitors for Alzheimer's disease, part 2: illustrating their mechanisms of action. The Journal of Clinical Psychiatry. 2000;61(11):813–814. doi:10.4088/JCP.v61n1101. PMID 11105732.
^Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, Booker L, Oremus M. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Annals of Internal Medicine. 2008;148(5):379–397. doi:10.7326/0003-4819-148-5-200803040-00009. PMID 18316756.
Ballard C, Waite J. The Effectiveness of Atypical Antipsychotics for the Treatment of Aggression and Psychosis in Alzheimer's Disease. The Cochrane Database of Systematic Reviews. 2006;(1):CD003476. doi:10.1002/14651858.CD003476.pub2. PMID 16437455.
^ abcdefgRabins PV, Blacker D, Rovner BW, Rummans T, Schneider LS, Tariot PN, Blass DM, McIntyre JS, Charles SC, Anzia DJ, Cook IA, Finnerty MT, Johnson BR, Nininger JE, Schneidman B, Summergrad P, Woods SM, Berger J, Cross CD, Brandt HA, Margolis PM, Shemo JP, Blinder BJ, Duncan DL, Barnovitz MA, Carino AJ, Freyberg ZZ, Gray SH, Tonnu T, Kunkle R, Albert AB, Craig TJ, Regier DA, Fochtmann LJ. American Psychiatric Association practice guideline for the treatment of patients with Alzheimer's disease and other dementias. The American Journal of Psychiatry. December 2007;164(12 Suppl):5–56. PMID 18340692.
^Bottino CM, Carvalho IA, Alvarez AM, Avila R, Zukauskas PR, Bustamante SE, Andrade FC, Hototian SR, Saffi F, Câmargo CH. Cognitive rehabilitation combined with drug treatment in Alzheimer's disease patients: a pilot study. Clinical Rehabilitation. 2005;19(8):861–869. doi:10.1191/0269215505cr911oa. PMID 16323385.
^Doody RS, Stevens JC, Beck C, Dubinsky RM, Kaye JA, Gwyther L, Mohs RC, Thal LJ, Whitehouse PJ, DeKosky ST, Cummings JL. Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001;56(9):1154–1166. doi:10.1212/WNL.56.9.1154. PMID 11342679.
^Hermans DG, Htay UH, McShane R. Non-pharmacological interventions for wandering of people with dementia in the domestic setting. The Cochrane Database of Systematic Reviews. 2007;(1):CD005994. doi:10.1002/14651858.CD005994.pub2. PMID 17253573.
^Robinson L, Hutchings D, Dickinson HO, Corner L, Beyer F, Finch T, Hughes J, Vanoli A, Ballard C, Bond J. Effectiveness and acceptability of non-pharmacological interventions to reduce wandering in dementia: a systematic review. International Journal of Geriatric Psychiatry. 2007;22(1):9–22. doi:10.1002/gps.1643. PMID 17096455.
^Zetteler J. Effectiveness of simulated presence therapy for individuals with dementia: a systematic review and meta-analysis. Aging & Mental Health. November 2008;12(6):779–85. doi:10.1080/13607860802380631. PMID 19023729.
^Spector A, Thorgrimsen L, Woods B, Royan L, Davies S, Butterworth M, Orrell M. Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia: randomised controlled trial. The British Journal of Psychiatry. 2003;183(3):248–254. doi:10.1192/bjp.183.3.248. PMID 12948999.
^Gitlin LN, Hauck WW, Dennis MP, Winter L. Maintenance of Effects of the Home Environmental Skill-building Program for Family Caregivers and Individuals with Alzheimer's Disease and Related Disorders. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2005;60(3):368–74. doi:10.1093/gerona/60.3.368. PMID 15860476.
Friedlander AH, Norman DC, Mahler ME, Norman KM, Yagiela JA. Alzheimer's Disease: Psychopathology, Medical Management and Dental Implications. Journal of the American Dental Association (1939). 2006;137(9):1240–51. PMID 16946428.
Belmin J. Practical Guidelines for the Diagnosis and Management of Weight Loss in Alzheimer's Disease: A Consensus from Appropriateness Ratings of a Large Expert Panel. The Journal of Nutrition, Health & Aging. 2007;11(1):33–7. PMID 17315078.
McCurry SM, Gibbons LE, Logsdon RG, Vitiello M, Teri L. Training Caregivers to Change the Sleep Hygiene Practices of Patients with Dementia: The NITE-AD Project. Journal of the American Geriatrics Society. 2003;51(10):1455–60. doi:10.1046/j.1532-5415.2003.51466.x. PMID 14511168.
Perls TT, Herget M. Higher Respiratory Infection Rates on an Alzheimer's Special Care Unit and successful intervention. Journal of the American Geriatrics Society. 1995;43(12):1341–4. PMID 7490383.
^Shega JW, Levin A, Hougham GW, Cox-Hayley D, Luchins D, Hanrahan P, Stocking C, Sachs GA. Palliative Excellence in Alzheimer Care Efforts (PEACE): A Program Description. Journal of Palliative Medicine. 2003;6(2):315–20. doi:10.1089/109662103764978641. PMID 12854952.
^ abBowen JD, Malter AD, Sheppard L, Kukull WA, McCormick WC, Teri L, Larson EB. Predictors of Mortality in Patients Diagnosed with Probable Alzheimer's Disease. Neurology. 1996;47(2):433–9. PMID 8757016.
^ abDodge HH, Shen C, Pandav R, DeKosky ST, Ganguli M. Functional Transitions and Active Life Expectancy Associated with Alzheimer Disease. Archives of Neurology. 2003;60(2):253–9. doi:10.1001/archneur.60.2.253. PMID 12580712.
^Larson EB, Shadlen MF, Wang L, McCormick WC, Bowen JD, Teri L, Kukull WA. Survival after Initial Diagnosis of Alzheimer Disease. Annals of Internal Medicine. 2004;140(7):501–9. PMID 15068977.
^ abcBermejo-Pareja F, Benito-León J, Vega S, Medrano MJ, Román GC. Incidence and subtypes of dementia in three elderly populations of central Spain. Journal of the Neurological Sciences. 2008;264(1–2):63–72. doi:10.1016/j.jns.2007.07.021. PMID 17727890.
^ abcDi Carlo A, Baldereschi M, Amaducci L, Lepore V, Bracco L, Maggi S, Bonaiuto S, Perissinotto E, Scarlato G, Farchi G, Inzitari D. Incidence of dementia, Alzheimer's disease, and vascular dementia in Italy. The ILSA Study. Journal of the American Geriatrics Society. 2002;50(1):41–8. doi:10.1046/j.1532-5415.2002.50006.x. PMID 12028245.
^Andersen K, Launer LJ, Dewey ME, Letenneur L, Ott A, Copeland JR, Dartigues JF, Kragh-Sorensen P, Baldereschi M, Brayne C, Lobo A, Martinez-Lage JM, Stijnen T, Hofman A. Gender Differences in the Incidence of AD and Vascular Dementia: The EURODEM Studies. EURODEM Incidence Research Group. Neurology. 1999;53(9):1992–7. PMID 10599770.
Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer Disease in the US population: Prevalence Estimates Using the 2000 census. Archives of Neurology. 2003;60(8):1119–22. doi:10.1001/archneur.60.8.1119. PMID 12925369.
Alzheimer Alois. Über eine eigenartige Erkrankung der Hirnrinde [About a peculiar disease of the cerebral cortex]. Allgemeine Zeitschrift fur Psychiatrie und Psychisch-Gerichtlich Medizin. 1907;64(1–2):146–148. (German).
Alzheimer Alois. About a Peculiar Disease of the Cerebral Cortex. Alzheimer Disease and Associated Disorders. 1987;1(1):3–8. PMID 3331112.
Maurer Ulrike, Maurer Konrad (2003). Alzheimer: The Life of a Physician and the Career of a Disease. New York: Columbia University Press. p. 270. ISBN0-231-11896-1.
^Berrios G E. Alzheimer's Disease: A Conceptual History. Int. J. Ger. Psychiatry. 1990;5(6):355–365. doi:10.1002/gps.930050603.
^Kraepelin Emil, Diefendorf A. Ross (translated by) (17 January 2007). Clinical Psychiatry: A Textbook For Students And Physicians (Reprint). Kessinger Publishing. p. 568. ISBN1-4325-0833-4.
^Katzman Robert, Terry Robert D, Bick Katherine L (editors) (1978). Alzheimer's Disease: Senile Dementia and Related Disorders. New York: Raven Press. p. 595. ISBN0-89004-225-X.
^Amaducci LA, Rocca WA, Schoenberg BS. Origin of the Distinction between Alzheimer's Disease and Senile Dementia: How History Can Clarify Nosology. Neurology. 1986;36(11):1497–9. PMID 3531918.
^Allegri RF, Butman J, Arizaga RL, Machnicki G, Serrano C, Taragano FE, Sarasola D, Lon L. Economic Impact of Dementia in Developing Countries: An Evaluation of Costs of Alzheimer-type Dementia in Argentina. International Psychogeriatrics. 2007;19(4):705–18. doi:10.1017/S1041610206003784. PMID 16870037.
^Suh GH, Knapp M, Kang CJ. The Economic Costs of Dementia in Korea, 2002. International Journal of Geriatric Psychiatry. 2006;21(8):722–8. doi:10.1002/gps.1552. PMID 16858741.
^Wimo A, Jonsson L, Winblad B. An Estimate of the Worldwide Prevalence and Direct Costs of Dementia in 2003. Dementia and Geriatric Cognitive Disorders. 2006;21(3):175–81. doi:10.1159/000090733. PMID 16401889.
^ abcMoore MJ, Zhu CW, Clipp EC. Informal Costs of Dementia Care: Estimates from the National Longitudinal Caregiver Study. The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences. 2001;56(4):S219–28. doi:10.1093/geronb/56.4.S219. PMID 11445614.
^Jönsson L, Eriksdotter Jönhagen M, Kilander L, Soininen H, Hallikainen M, Waldemar G, Nygaard H, Andreasen N, Winblad B, Wimo A. Determinants of Costs of Care for Patients with Alzheimer's Disease. International Journal of Geriatric Psychiatry. 2006;21(5):449–59. doi:10.1002/gps.1489. PMID 16676288.
^Gaugler JE, Kane RL, Kane RA, Newcomer R. Early Community-based Service Utilization and Its Effects on Institutionalization in Dementia Caregiving. The Gerontologist. 2005;45(2):177–85. doi:10.1093/geront/45.2.177. PMID 15799982.
^Brodaty H, Hadzi-Pavlovic D. Psychosocial Effects on Carers of Living with Persons with Dementia. The Australian and New Zealand Journal of Psychiatry. 1990;24(3):351–61. doi:10.3109/00048679009077702. PMID 2241719.
^Pusey H, Richards D. A Systematic Review of the Effectiveness of Psychosocial Interventions for Carers of People with Dementia. Aging & Mental Health. 2001;5(2):107–19. doi:10.1080/13607860120038302. PMID 11511058.
^Harrington Charles. Methylthioninium Chloride (MTC) Acts as a Tau Aggregation Inhibitor (TAI) in a Cellular Model and Reverses Tau Pathology in Transgenic Mouse Models of Alzheimer's Disease. Alzheimer's & Dementia. 2008;4(4):T120–T121. doi:10.1016/j.jalz.2008.05.259.
^Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D. Effect of Dimebon on Cognition, Activities of Daily Living, Behaviour, and Global Function in Patients with Mild-to-moderate Alzheimer's Disease: A Randomised, Double-blind, Placebo-controlled study. Lancet. 2008;372(9634):207–15. doi:10.1016/S0140-6736(08)61074-0. PMID 18640457.
^ abMartin C, Solís L, Concha MI, Otth C. Herpes simplex virus tipo 1 como factor de riesgo asociado con la enfermedad de Alzheimer [Herpes Simplex Virus Type 1 as Risk Factor Associated to Alzheimer Disease]. Revista Médica De Chile. June 2011;139(6):779–86. Spanish. doi:10.4067/S0034-98872011000600013. PMID 22051760.
^Wozniak MA, Mee AP, Itzhaki RF. Herpes Simplex Virus type 1 DNA Is Located within Alzheimer's Disease Amyloid Plaques. The Journal of Pathology. 2008;217(1):131–138. doi:10.1002/path.2449. PMID 18973185.
^Dougall NJ, Bruggink S, Ebmeier KP. Systematic Review of the Diagnostic Accuracy of 99mTc-HMPAO-SPECT in Dementia. The American Journal of Geriatric Psychiatry. 2004;12(6):554–70. doi:10.1176/appi.ajgp.12.6.554. PMID 15545324.
^Carpenter AP, Pontecorvo MJ, Hefti FF, Skovronsky DM. The Use of the Exploratory IND in the Evaluation and Development of18F-PET Radiopharmaceuticals for Amyloid Imaging in the Brain: A Review of One Company's Experience. The Quarterly Journal of Nuclear Medicine and Molecular Imaging. August 2009;53(4):387–93. PMID 19834448.