Get Alzheimer's Disease essential facts below. View Videos or join the Alzheimer's Disease discussion. Add Alzheimer's Disease to your PopFlock.com topic list for future reference or share this resource on social media.
Progressive, neurodegenerative disease characterized by memory loss
Alzheimer disease, Alzheimer's
Comparison of a normal aged brain (left) and the brain of a person with Alzheimer's (right). Characteristics that separate the two are pointed out.
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. Behavioural 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.
In 2015, there were approximately 29.8 million people worldwide with AD. It most often begins in people over 65 years of age, although 4-5% of cases are early-onset Alzheimer's. It affects about 6% of people 65 years and older. In 2015, dementia resulted in about 1.9 million deaths. It was first described by, and later named after, German psychiatrist and pathologist Alois Alzheimer in 1906. In developed countries, AD is one of the most financially costly diseases.
Subtle problems with the executive functions of attentiveness, planning, flexibility, and abstract thinking, or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of the early stages of AD.Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease. Depressive symptoms, irritability and reduced awareness of subtle memory difficulties are also common.
The preclinical stage of the disease has also been termed mild cognitive impairment (MCI). This is often found to be a transitional stage between normal ageing and dementia. MCI can present with a variety of symptoms, and when memory loss is the predominant symptom, it is termed "amnestic MCI" and is frequently seen as a prodromal stage of Alzheimer's disease.
In people with AD, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small percentage, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems. AD does not affect all memory capacities equally. Older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat or how to drink from a glass) are affected to a lesser degree than new facts or 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 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 stages, 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.
The cause for most Alzheimer's cases is still mostly unknown except for 1% to 5% of cases where genetic differences have been identified. Several competing hypotheses exist trying to explain the cause of the disease.
The genetic heritability of Alzheimer's disease (and memory components thereof), based on reviews of twin and family studies, ranges from 49% to 79%. Around 0.1% of the cases are familial forms of autosomal (not sex-linked) dominant inheritance, which have an onset before age 65. This form of the disease is known as early onset familial Alzheimer's disease. Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: those encoding amyloid precursor protein (APP) and presenilins 1 and 2. Most mutations in the APP and presenilin genes increase the production of a small protein called A?42, which is the main component of senile plaques. Some of the mutations merely alter the ratio between A?42 and the other major forms--particularly A?40--without increasing A?42 levels. Two other genes associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1.
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 ?4 allele of the apolipoprotein E (APOE). Between 40 and 80% of people with AD possess at least one APOE?4 allele. The APOE?4 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 APOE?4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations. Early attempts to screen up to 400 candidate genes for association with late-onset sporadic AD (LOAD) resulted in a low yield. More recent genome-wide association studies (GWAS) have found 19 areas in genes that appear to affect the risk. These genes include: CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B, SORL1, ZCWPW1, SLC24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, and CD2AP.
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 beta amyloid present. Many single-nucleotide polymorphisms (SNPs) are associated with Alzheimer's, with a 2018 study adding 30 SNPs by differentiating AD into 6 categories, including memory, language, visuospatial, and executive functioning.
The oldest hypothesis, 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.
In 1991, the amyloid hypothesis postulated that extracellular amyloid beta (A?) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of AD by 40 years of age. Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. While apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain. Further evidence comes from the finding that transgenic mice that express a mutant form of the human APP gene develop fibrillar amyloid plaques and Alzheimer's-like brain pathology with spatial learning deficits.
An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia. Researchers have been led to suspect non-plaque A?oligomers (aggregates of many monomers) as the primary pathogenic form of A?. 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 A? 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 hypothesis 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 hypothesis 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.
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. This mutation is known as the Osaka mutation. Only homozygotes with this mutation develop Alzheimer's disease. This mutation accelerates A? oligomerization but the proteins do not form amyloid fibrils suggesting that it is the A? oligomerization rather than the fibrils that may be the cause of this disease. Mice expressing this mutation have all usual pathologies of Alzheimer's disease.
In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.
The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system. This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.
An inflammatory hypothesis is that AD is caused due to a self-perpetuating progressive inflammation in the brain culminating in neurodegeneration. A possible role of chronic periodontal infection and the gut microbiota has been suggested.
The cellular homeostasis of biometals such as ionic copper, iron, and zinc is disrupted in AD, though it remains unclear whether this is produced by or causes the changes in proteins. These ions affect and are affected by tau, APP, and APOE, and their dysregulation may cause oxidative stress that may contribute to the pathology. The quality of some of these studies has been criticised, and the link remains controversial. The majority of researchers do not support a causal connection with aluminium.
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 AD go through a reverse neurodegeneration process starting with demyelination and death of axons (white matter) and ending with the death of grey matter. Likewise the hypothesis is, that as infants go through states of cognitive development, people with AD go through the reverse process of progressive cognitive impairment. Reisberg developed the caregiving assessment tool known as "FAST" (Functional Assessment Staging Tool) which he says allows those caring for people with AD 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 AD.
Histopathologic image of senile plaques seen in the cerebral cortex of a person with Alzheimer's disease of presenile onset. Silver impregnation.
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.
Exactly how disturbances of production and aggregation of the beta-amyloid peptide give rise to the pathology of AD is not known.
The amyloid hypothesis traditionally points to the accumulation of beta-amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calciumionhomeostasis, induces programmed cell death (apoptosis). It is also known that A? selectively builds up in the mitochondria in the cells of Alzheimer's-affected brains, and it also inhibits certain enzyme functions and the utilisation of glucose by neurons.
Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer's disease. Inflammation is a general marker of tissue damage in any disease, and may be either secondary to tissue damage in AD or a marker of an immunological response. There is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression.
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. (It is also necessary to rule out delirium).
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 ¹?F-FDG PET scans, as a single test, to identify people who may develop Alzheimer's disease is also not supported by evidence.
Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.
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.
People who engage in intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instruments, or regular social interaction show a reduced risk for Alzheimer's disease. This is compatible with the cognitive reserve theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations.Education delays the onset of AD syndrome without changing the duration of the disease. Learning a second language even later in life seems to delay the onset of Alzheimer's disease.Physical activity is also associated with a reduced risk of AD. Physical exercise is associated with decreased rate of dementia. Physical exercise is also effective in reducing symptom severity in those with Alzheimer's disease.
Conclusions on dietary components have at times been difficult to ascertain as results have differed between population-based studies and randomised controlled trials. There is limited evidence that light to moderate use of alcohol, particularly red wine, is associated with lower risk of AD. There is tentative evidence that caffeine may be protective. A number of foods high in flavonoids such as cocoa, red wine, and tea may decrease the risk of AD.
Reviews on the use of vitamins and minerals have not found enough consistent evidence to recommend them. This includes vitamin A, C, the alpha-tocopherol form of vitamin E,selenium,zinc, and folic acid with or without vitamin B12. Evidence from one randomized controlled trial indicated that the alpha-tocopherol form of vitamin E may slow cognitive decline, this evidence was judged to be "moderate" in quality. Trials examining folic acid (B9) and other B vitamins failed to show any significant association with cognitive decline. Omega-3 fatty acid supplements from plants and fish, and dietary docosahexaenoic acid (DHA), do not appear to benefit people with mild to moderate Alzheimer's disease.
Curcumin as of 2010[update] had not shown benefit in people even though there is tentative evidence in animals. There was inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment and dementia. As of 2008[update] there was no concrete evidence that cannabinoids are effective in improving the symptoms of AD or dementia; however, some research into endocannabinoids looked 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. The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD. The most common side effects are nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately 10-20% of users, are mild to moderate in severity, and can be managed by slowly adjusting medication doses. Less common secondary effects include muscle cramps, decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid production.
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. Music therapy is effective in reducing behavioural 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 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 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 labelling of household items to cue the person with the disease or the use of modified daily life objects. If eating becomes problematic, food will need to be prepared in smaller pieces or even pureed. When swallowing difficulties arise, the use of feeding tubes may be required. In such cases, the medical efficacy and ethics of continuing feeding is an important consideration of the caregivers and family members. The use of physical restraints is rarely indicated in any stage of the disease, although there are situations when they are necessary to prevent harm to the person with AD or their caregivers.
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.
Fewer than 3% of people live more than fourteen years. Disease features significantly associated with reduced survival are an increased severity of cognitive impairment, decreased functional level, history of falls, and disturbances in the neurological examination. Other coincident diseases such as heart problems, diabetes or history of alcohol abuse are also related with shortened survival. While the earlier the age at onset the higher the total survival years, life expectancy is particularly reduced when compared to the healthy population among those who are younger. Men have a less favourable survival prognosis than women.
Pneumonia and dehydration are the most frequent immediate causes of death brought by AD, while cancer is a less frequent cause of death than in the general population.
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. 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.
Deaths per million persons in 2012 due to dementias including Alzheimer's disease
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 , range ) 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, 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 preseniledementia by Kraepelin, as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published on 1910.
For most of the 20th century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference on AD concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility that they had different causes. This eventually led to the diagnosis of Alzheimer's disease independent of age. The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used to describe those who were younger. Eventually, the 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 costs in other countries such as Argentina, and South Korea, are also high and rising. These costs will probably increase with the ageing of society, becoming an important social problem. AD-associated costs include direct medical costs such as nursing home care, direct nonmedical costs such as in-home day care, and indirect costs such as lost productivity of both patient and caregiver. Numbers vary between studies but dementia costs worldwide have been calculated around $160 billion, while 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.
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 2008, two separate clinical trials showed positive results in modifying the course of disease in mild to moderate AD with methylthioninium chloride, a drug that inhibits tau aggregation, and dimebon, an antihistamine.
The consecutive phase-III trial of dimebon failed to show positive effects in the primary and secondary endpoints. Work with methylthioninium chloride showed that bioavailability of methylthioninium from the gut was affected by feeding and by stomach acidity, leading to unexpectedly variable dosing. A new stabilised formulation, as the prodrugLMTX, is in phase-III trials (in 2014).
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. However, in October 2019, an analysis of another dataset found that aducanumab may reduce clinical decline in people with early Alzheimer's disease and the Biogen company may seek regulatory approval again.
The senescence accelerated mouse (SAMP8) is an Alzheimer's disease (AD) animal model in which amyloid precursor protein (APP) is overproduced. The mice develops early memory disturbances and alters the blood-brain barrier, which causes a decreased expulsion of amyloid-? 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-? (antisense to APP and antibodies to amyloid-?) 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-? overproduction in this AD 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.
Fungal infection of AD brain has also been described.
This hypothesis was proposed by the microbiologist L. Carrasco when his group found statistical correlation between disseminated mycoses and AD.
Further work revealed that fungal infection is present in different brain regions of AD patients, but not in the control individuals.
A fungal infection explains the symptoms observed in AD patients. The slow progression of AD fits with the chronic nature of some systemic fungal infections, which can be asymptomatic and thus, unnoticed and untreated.
The fungal hypotheses are also compatible with some other established AD hypotheses, like the amyloid hypothesis, that can be explained as an immune system response to an infection in the CNS, as found by R. Moir and R. Tanzi in mouse and worm models of AD.
This section needs to be updated. Please update this article to reflect recent events or newly available information. Last update: from PMID28072381 and PMID28259856(April 2018)
Amyloid imaging is likely to be used in conjunction with other markers rather than as an alternative. Volumetric MRI can detect changes in the size of brain regions. Measuring those regions that atrophy during the progress of Alzheimer's disease is showing promise as a diagnostic indicator. It may prove less expensive than other imaging methods currently under study.
In 2011, an FDA panel voted unanimously to recommend approval of florbetapir. The imaging agent can help to detect Alzheimer's brain plaques. A negative scan indicates sparse or no plaques, which is not consistent with a diagnosis of AD.
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 ageing-related breakdown of the blood-brain barrier may be causative of AD, and conclude that markers for that damage may be an early predictor of the disease.
^Commission de la transparence (June 2012). "Drugs for Alzheimer's disease: best avoided. No therapeutic advantage" [Drugs for Alzheimer's disease: best avoided. No therapeutic advantage]. Prescrire International. 21 (128): 150. PMID22822592.
^Todd S, Barr S, Roberts M, Passmore AP (November 2013). "Survival in dementia and predictors of mortality: a review". International Journal of Geriatric Psychiatry. 28 (11): 1109-24. doi:10.1002/gps.3946. PMID23526458.
^ abcBerchtold NC, Cotman CW (1998). "Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s". Neurobiology of Aging. 19 (3): 173-89. doi:10.1016/S0197-4580(98)00052-9. PMID9661992.
^ abcdeWaldemar G, Dubois B, Emre M, Georges J, McKeith IG, Rossor M, Scheltens P, Tariska P, Winblad B (January 2007). "Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline". European Journal of Neurology. 14 (1): e1-26. doi:10.1111/j.1468-1331.2006.01605.x. PMID17222085.
^Nygård L (2003). "Instrumental activities of daily living: a stepping-stone towards Alzheimer's disease diagnosis in subjects with mild cognitive impairment?". Acta Neurologica Scandinavica. Supplementum. 179 (s179): 42-6. doi:10.1034/j.1600-0404.107.s179.8.x. PMID12603250.
^Murray ED, Buttner N, Price BH (2012). "Depression and Psychosis in Neurological Practice". In Bradley WG, Daroff RB, Fenichel GM, Jankovic J (eds.). Bradley's neurology in clinical practice (6th ed.). Philadelphia, PA: Elsevier/Saunders. ISBN978-1-4377-0434-1.
^Grundman M, Petersen RC, Ferris SH, Thomas RG, Aisen PS, Bennett DA, et al. (January 2004). "Mild cognitive impairment can be distinguished from Alzheimer disease and normal aging for clinical trials". Archives of Neurology. 61 (1): 59-66. doi:10.1001/archneur.61.1.59. PMID14732621.
^Carlesimo GA, Oscar-Berman M (June 1992). "Memory deficits in Alzheimer's patients: a comprehensive review". Neuropsychology Review. 3 (2): 119-69. doi:10.1007/BF01108841. PMID1300219.
^Jelicic M, Bonebakker AE, Bonke B (1995). "Implicit memory performance of patients with Alzheimer's disease: a brief review". International Psychogeriatrics. 7 (3): 385-92. doi:10.1017/S1041610295002134. PMID8821346.
^ abTaler V, Phillips NA (July 2008). "Language performance in Alzheimer's disease and mild cognitive impairment: a comparative review". Journal of Clinical and Experimental Neuropsychology. 30 (5): 501-56. doi:10.1080/13803390701550128. PMID18569251.
^ abcFrank EM (September 1994). "Effect of Alzheimer's disease on communication function". Journal of the South Carolina Medical Association. 90 (9): 417-23. PMID7967534.
^Gold DP, Reis MF, Markiewicz D, Andres D (January 1995). "When home caregiving ends: a longitudinal study of outcomes for caregivers of relatives with dementia". Journal of the American Geriatrics Society. 43 (1): 10-6. doi:10.1111/j.1532-5415.1995.tb06235.x. PMID7806732.
^Hardy J, Allsop D (October 1991). "Amyloid deposition as the central event in the aetiology of Alzheimer's disease". Trends in Pharmacological Sciences. 12 (10): 383-88. doi:10.1016/0165-6147(91)90609-V. PMID1763432.
^Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, Niinistö L, Halonen P, Kontula K (November 1995). "Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein". The New England Journal of Medicine. 333 (19): 1242-47. doi:10.1056/NEJM199511093331902. PMID7566000.
Lalonde R, Dumont M, Staufenbiel M, Sturchler-Pierrat C, Strazielle C (November 2002). "Spatial learning, exploration, anxiety, and motor coordination in female APP23 transgenic mice with the Swedish mutation". Brain Research. 956 (1): 36-44. doi:10.1016/S0006-8993(02)03476-5. PMID12426044.
^Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA (July 2008). "Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial". Lancet. 372 (9634): 216-23. doi:10.1016/S0140-6736(08)61075-2. PMID18640458.
^Tomiyama T (2010). "Involvement of beta-amyloid in the etiology of Alzheimer's disease". Brain Nerve. 62 (7): 691-699. PMID20675873.
^Tomiyama T, Nagata T, Shimada H, Teraoka R, Fukushima A, Kanemitsu H, Takuma H, Kuwano R, Imagawa M, Ataka S, Wada Y, Yoshioka E, Nishizaki T, Watanabe Y, Mori H (2008). "A new amyloid beta variant favoring oligomerization in Alzheimer's-type dementia". Ann Neurol. 63 (3): 377-387. doi:10.1002/ana.21321. PMID18300294.CS1 maint: multiple names: authors list (link)
^Iqbal K, Alonso A, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I (January 2005). "Tau pathology in Alzheimer disease and other tauopathies". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1739 (2-3): 198-210. doi:10.1016/j.bbadis.2004.09.008. PMID15615638.
^ abKamer, Angela R.; Craig, Ronald G.; Dasanayake, Ananda P.; Brys, Miroslaw; Glodzik-Sobanska, Lidia; de Leon, Mony J. (July 2008). "Inflammation and Alzheimer's disease: Possible role of periodontal diseases". Alzheimer's & Dementia. 4 (4): 242-250. doi:10.1016/j.jalz.2007.08.004. PMID18631974.
^Eikelenboom P, van Exel E, Hoozemans JJ, Veerhuis R, Rozemuller AJ, van Gool WA (2010). "Neuroinflammation - an early event in both the history and pathogenesis of Alzheimer's disease". Neuro-Degenerative Diseases. 7 (1-3): 38-41. doi:10.1159/000283480. PMID20160456.
^ abcReisberg B, Franssen EH, Hasan SM, Monteiro I, Boksay I, Souren LE, et al. (1999). "Retrogenesis: clinical, physiologic, and pathologic mechanisms in brain aging, Alzheimer's and other dementing processes". European Archives of Psychiatry and Clinical Neuroscience. 249 Suppl 3 (3): 28-36. doi:10.1007/pl00014170. PMID10654097.
^Brenner Carson, Verna (2015). Caregiving for Alzheimer's Disease. New York: Springer New York Academy of Sciences. pp. 1-9. ISBN978-1-4939-2406-6.
^Zis, Panagiotis; Hadjivassiliou, Marios (26 February 2019). "Treatment of Neurological Manifestations of Gluten Sensitivity and Coeliac Disease". Current Treatment Options in Neurology. 21 (3): 10. doi:10.1007/s11940-019-0552-7. PMID30806821.
^Makhlouf S, Messelmani M, Zaouali J, Mrissa R (2018). "Cognitive impairment in celiac disease and non-celiac gluten sensitivity: review of literature on the main cognitive impairments, the imaging and the effect of gluten free diet". Acta Neurol Belg (Review). 118 (1): 21-27. doi:10.1007/s13760-017-0870-z. PMID29247390.
^Wenk GL (2003). "Neuropathologic changes in Alzheimer's disease". The Journal of Clinical Psychiatry. 64 Suppl 9: 7-10. PMID12934968.
^Kotzbauer PT, Trojanowsk JQ, Lee VM (October 2001). "Lewy body pathology in Alzheimer's disease". Journal of Molecular Neuroscience. 17 (2): 225-32. doi:10.1385/JMN:17:2:225. PMID11816795.
^Hashimoto M, Rockenstein E, Crews L, Masliah E (2003). "Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases". Neuromolecular Medicine. 4 (1-2): 21-36. doi:10.1385/NMM:4:1-2:21. PMID14528050.
^Turner PR, O'Connor K, Tate WP, Abraham WC (May 2003). "Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory". Progress in Neurobiology. 70 (1): 1-32. doi:10.1016/S0301-0082(03)00089-3. PMID12927332.
^Hooper NM (April 2005). "Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein". Biochemical Society Transactions. 33 (Pt 2): 335-38. doi:10.1042/BST0330335. PMID15787600. S2CID14269634.
^Van Broeck B, Van Broeckhoven C, Kumar-Singh S (2007). "Current insights into molecular mechanisms of Alzheimer disease and their implications for therapeutic approaches". Neuro-Degenerative Diseases. 4 (5): 349-65. doi:10.1159/000105156. PMID17622778.
^ abMcKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (July 1984). "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. 34 (7): 939-44. doi:10.1212/wnl.34.7.939. PMID6610841.
^ abDubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. (August 2007). "Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria". The Lancet. Neurology. 6 (8): 734-46. doi:10.1016/S1474-4422(07)70178-3. PMID17616482.
^Blacker D, Albert MS, Bassett SS, Go RC, Harrell LE, Folstein MF (December 1994). "Reliability and validity of NINCDS-ADRDA criteria for Alzheimer's disease. The National Institute of Mental Health Genetics Initiative". Archives of Neurology. 51 (12): 1198-204. doi:10.1001/archneur.1994.00540240042014. PMID7986174.
^American Psychiatric Association (2000). Diagnostic and statistical manual of mental disorders: DSM-IV-TR (4th Edition Text Revision ed.). Washington, DC: American Psychiatric Association. ISBN978-0-89042-025-6.
^Ito N (May 1996). "[Clinical aspects of dementia]". [Hokkaido Igaku Zasshi] the Hokkaido Journal of Medical Science (in Japanese). 71 (3): 315-20. PMID8752526.
^ abParadise M, Cooper C, Livingston G (February 2009). "Systematic review of the effect of education on survival in Alzheimer's disease". International Psychogeriatrics. 21 (1): 25-32. doi:10.1017/S1041610208008053. PMID19026089.
^Solfrizzi V, Capurso C, D'Introno A, Colacicco AM, Santamato A, Ranieri M, Fiore P, Capurso A, Panza F (January 2008). "Lifestyle-related factors in predementia and dementia syndromes". Expert Review of Neurotherapeutics. 8 (1): 133-58. doi:10.1586/14737126.96.36.199. PMID18088206.
^Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N (2010). "Caffeine intake and dementia: systematic review and meta-analysis". Journal of Alzheimer's Disease. 20 Suppl 1: S187-204. doi:10.3233/JAD-2010-091387. PMID20182026.
^Lerner AJ, Gustaw-Rothenberg K, Smyth S, Casadesus G (March-April 2012). "Retinoids for treatment of Alzheimer's disease". BioFactors. 38 (2): 84-89. doi:10.1002/biof.196. PMID22419567.
^Heo JH, Lee KM (March 2013). "The possible role of antioxidant vitamin C in Alzheimer's disease treatment and prevention". American Journal of Alzheimer's Disease and Other Dementias (Review). 28 (2): 120-25. doi:10.1177/1533317512473193. PMID23307795.
^Boothby LA, Doering PL (December 2005). "Vitamin C and vitamin E for Alzheimer's disease". The Annals of Pharmacotherapy. 39 (12): 2073-80. doi:10.1345/aph.1E495. PMID16227450.
^Malouf R, Grimley Evans J (October 2008). "Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people". The Cochrane Database of Systematic Reviews (4): CD004514. doi:10.1002/14651858.CD004514.pub2. PMID18843658.
^Wald DS, Kasturiratne A, Simmonds M (June 2010). "Effect of folic acid, with or without other B vitamins, on cognitive decline: meta-analysis of randomized trials". The American Journal of Medicine. 123 (6): 522-527.e2. doi:10.1016/j.amjmed.2010.01.017. PMID20569758.
^Cunnane SC, Chouinard-Watkins R, Castellano CA, Barberger-Gateau P (January 2013). "Docosahexaenoic acid homeostasis, brain aging and Alzheimer's disease: Can we reconcile the evidence?". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 88 (1): 61-70. doi:10.1016/j.plefa.2012.04.006. PMID22575581.
^Fink, Howard A.; Linskens, Eric J.; MacDonald, Roderick; Silverman, Pombie C.; McCarten, J. Riley; Talley, Kristine M.C.; Forte, Mary L.; Desai, Priyanka J.; Nelson, Victoria A.; Miller, Margaret A.; Hemmy, Laura S.; Brasure, Michelle; Taylor, Brent C.; Ng, Weiwen; Ouellette, Jeannine M.; Sheets, Kerry M.; Wilt, Timothy J.; Butler, Mary (28 April 2020). "Benefits and Harms of Prescription Drugs and Supplements for Treatment of Clinical Alzheimer-Type Dementia". Annals of Internal Medicine. 172 (10): 656-668. doi:10.7326/M19-3887. PMID32340037.
^Stahl SM (November 2000). "The new cholinesterase inhibitors for Alzheimer's disease, Part 2: illustrating their mechanisms of action". The Journal of Clinical Psychiatry. 61 (11): 813-14. doi:10.4088/JCP.v61n1101. PMID11105732.
^Alldredge BK, Corelli RL, Ernst ME, Guglielmo BJ, Jacobson PA, Kradjan WA, Williams BR (2013). Applied therapeutics : the clinical use of drugs (10th ed.). Baltimore: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 2385. ISBN978-1-60913-713-7.
^ abLipton SA (February 2006). "Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond". Nature Reviews. Drug Discovery. 5 (2): 160-70. doi:10.1038/nrd1958. PMID16424917.
^"Memantine". US National Library of Medicine (Medline). 4 January 2004. Archived from the original on 22 February 2010. Retrieved 2010.
^Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, Booker L, Oremus M (March 2008). "Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline". Annals of Internal Medicine. 148 (5): 379-97. doi:10.7326/0003-4819-148-5-200803040-00009. PMID18316756.
^Ballard C, Waite J (January 2006). Ballard CG (ed.). "The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease". The Cochrane Database of Systematic Reviews (1): CD003476. doi:10.1002/14651858.CD003476.pub2. PMID16437455.
^Ballard C, Hanney ML, Theodoulou M, Douglas S, McShane R, Kossakowski K, Gill R, Juszczak E, Yu LM, Jacoby R (February 2009). "The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial". The Lancet Neurology. 8 (2): 151-57. doi:10.1016/S1474-4422(08)70295-3. PMID19138567. Lay summary.
^ abcdefgRabins PV, Blacker D, Rovner BW, Rummans T, Schneider LS, Tariot PN, et al. (Steering Committee on Practice Guidelines) (December 2007). "American Psychiatric Association practice guideline for the treatment of patients with Alzheimer's disease and other dementias. Second edition". The American Journal of Psychiatry. 164 (12 Suppl): 5-56. PMID18340692.
^Bottino CM, Carvalho IA, Alvarez AM, Avila R, Zukauskas PR, Bustamante SE, et al. (December 2005). "Cognitive rehabilitation combined with drug treatment in Alzheimer's disease patients: a pilot study". Clinical Rehabilitation. 19 (8): 861-69. doi:10.1191/0269215505cr911oa. PMID16323385.
^Doody RS, Stevens JC, Beck C, Dubinsky RM, Kaye JA, Gwyther L, et al. (May 2001). "Practice parameter: management of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology. 56 (9): 1154-66. doi:10.1212/WNL.56.9.1154. PMID11342679.
^Chung JC, Lai CK, Chung PM, French HP (2002). Chung JC (ed.). "Snoezelen for dementia". The Cochrane Database of Systematic Reviews (4): CD003152. doi:10.1002/14651858.CD003152. PMID12519587. (up to date as of 2009)
^Spector A, Thorgrimsen L, Woods B, Royan L, Davies S, Butterworth M, Orrell M (September 2003). "Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia: randomised controlled trial". The British Journal of Psychiatry. 183 (3): 248-54. doi:10.1192/bjp.183.3.248. PMID12948999.
^Gitlin LN, Corcoran M, Winter L, Boyce A, Hauck WW (February 2001). "A randomized, controlled trial of a home environmental intervention: effect on efficacy and upset in caregivers and on daily function of persons with dementia". The Gerontologist. 41 (1): 4-14. doi:10.1093/geront/41.1.4. PMID11220813.
^Gitlin LN, Hauck WW, Dennis MP, Winter L (March 2005). "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. 60 (3): 368-74. doi:10.1093/gerona/60.3.368. PMID15860476.
Friedlander AH, Norman DC, Mahler ME, Norman KM, Yagiela JA (September 2006). "Alzheimer's disease: psychopathology, medical management and dental implications". Journal of the American Dental Association. 137 (9): 1240-51. doi:10.14219/jada.archive.2006.0381. PMID16946428.
Belmin J (2007). "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. 11 (1): 33-37. PMID17315078.
McCurry SM, Gibbons LE, Logsdon RG, Vitiello M, Teri L (October 2003). "Training caregivers to change the sleep hygiene practices of patients with dementia: the NITE-AD project". Journal of the American Geriatrics Society. 51 (10): 1455-60. doi:10.1046/j.1532-5415.2003.51466.x. PMID14511168.
Perls TT, Herget M (December 1995). "Higher respiratory infection rates on an Alzheimer's special care unit and successful intervention". Journal of the American Geriatrics Society. 43 (12): 1341-44. doi:10.1111/j.1532-5415.1995.tb06611.x. PMID7490383.
^Shega JW, Levin A, Hougham GW, Cox-Hayley D, Luchins D, Hanrahan P, Stocking C, Sachs GA (April 2003). "Palliative Excellence in Alzheimer Care Efforts (PEACE): a program description". Journal of Palliative Medicine. 6 (2): 315-20. doi:10.1089/109662103764978641. PMID12854952. S2CID6072807.
^Jagger C, Clarke M, Stone A (January 1995). "Predictors of survival with Alzheimer's disease: a community-based study". Psychological Medicine. 25 (1): 171-77. doi:10.1017/S0033291700028191. PMID7792352.
^Dodge HH, Shen C, Pandav R, DeKosky ST, Ganguli M (February 2003). "Functional transitions and active life expectancy associated with Alzheimer disease". Archives of Neurology. 60 (2): 253-59. doi:10.1001/archneur.60.2.253. PMID12580712.
^ abGanguli M, Dodge HH, Shen C, Pandav RS, DeKosky ST (May 2005). "Alzheimer disease and mortality: a 15-year epidemiological study". Archives of Neurology. 62 (5): 779-84. doi:10.1001/archneur.62.5.779. PMID15883266.
^ abcBermejo-Pareja F, Benito-León J, Vega S, Medrano MJ, Román GC (January 2008). "Incidence and subtypes of dementia in three elderly populations of central Spain". Journal of the Neurological Sciences. 264 (1-2): 63-72. doi:10.1016/j.jns.2007.07.021. PMID17727890.
^ abcDi Carlo A, Baldereschi M, Amaducci L, Lepore V, Bracco L, Maggi S, Bonaiuto S, Perissinotto E, Scarlato G, Farchi G, Inzitari D (January 2002). "Incidence of dementia, Alzheimer's disease, and vascular dementia in Italy. The ILSA Study". Journal of the American Geriatrics Society. 50 (1): 41-48. doi:10.1046/j.1532-5415.2002.50006.x. PMID12028245.
^Andersen K, Launer LJ, Dewey ME, Letenneur L, Ott A, Copeland JR, et al. (December 1999). "Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group". Neurology. 53 (9): 1992-97. doi:10.1212/wnl.53.9.1992. PMID10599770.
Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA (August 2003). "Alzheimer disease in the US population: prevalence estimates using the 2000 census". Archives of Neurology. 60 (8): 1119-22. doi:10.1001/archneur.60.8.1119. PMID12925369.
"Highlights"(PDF). World Population Prospects: The 2006 Revision. Working Paper No. ESA/P/WP.202. Population Division, Department of Economic and Social Affairs, United Nations. 2007. Archived from the original(PDF) on 19 August 2008. Retrieved 2008.
Alzheimer A (1907). "Über eine eigenartige Erkrankung der Hirnrinde" [About a peculiar disease of the cerebral cortex]. Allgemeine Zeitschrift für Psychiatrie und Psychisch-Gerichtlich Medizin (in German). 64 (1-2): 146-48.
Alzheimer A (1987). Translated by H. Greenson. "About a peculiar disease of the cerebral cortex. By Alois Alzheimer, 1907 (Translated by L. Jarvik and H. Greenson)". Alzheimer Disease and Associated Disorders. 1 (1): 3-8. PMID3331112.
^Amaducci LA, Rocca WA, Schoenberg BS (November 1986). "Origin of the distinction between Alzheimer's disease and senile dementia: how history can clarify nosology". Neurology. 36 (11): 1497-9. doi:10.1212/wnl.36.11.1497. PMID3531918.
^Allegri RF, Butman J, Arizaga RL, Machnicki G, Serrano C, Taragano FE, Sarasola D, Lon L (August 2007). "Economic impact of dementia in developing countries: an evaluation of costs of Alzheimer-type dementia in Argentina". International Psychogeriatrics. 19 (4): 705-18. doi:10.1017/S1041610206003784. PMID16870037. S2CID41247271.
^Suh GH, Knapp M, Kang CJ (August 2006). "The economic costs of dementia in Korea, 2002". International Journal of Geriatric Psychiatry. 21 (8): 722-28. doi:10.1002/gps.1552. PMID16858741.
^Wimo A, Jonsson L, Winblad B (2006). "An estimate of the worldwide prevalence and direct costs of dementia in 2003". Dementia and Geriatric Cognitive Disorders. 21 (3): 175-81. doi:10.1159/000090733. PMID16401889.
^ abcMoore MJ, Zhu CW, Clipp EC (July 2001). "Informal costs of dementia care: estimates from the National Longitudinal Caregiver Study". The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences. 56 (4): S219-28. doi:10.1093/geronb/56.4.S219. PMID11445614.
^Jönsson L, Eriksdotter Jönhagen M, Kilander L, Soininen H, Hallikainen M, Waldemar G, et al. (May 2006). "Determinants of costs of care for patients with Alzheimer's disease". International Journal of Geriatric Psychiatry. 21 (5): 449-59. doi:10.1002/gps.1489. PMID16676288.
^Gaugler JE, Kane RL, Kane RA, Newcomer R (April 2005). "Early community-based service utilization and its effects on institutionalization in dementia caregiving". The Gerontologist. 45 (2): 177-85. doi:10.1093/geront/45.2.177. PMID15799982.
^Brodaty H, Hadzi-Pavlovic D (September 1990). "Psychosocial effects on carers of living with persons with dementia". The Australian and New Zealand Journal of Psychiatry. 24 (3): 351-61. doi:10.3109/00048679009077702. PMID2241719.
^Pusey H, Richards D (May 2001). "A systematic review of the effectiveness of psychosocial interventions for carers of people with dementia". Aging & Mental Health. 5 (2): 107-19. doi:10.1080/13607860120038302. PMID11511058.
^Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJ (November 2002). "New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease". The Journal of Biological Chemistry. 277 (45): 42881-90. doi:10.1074/jbc.M206593200. PMID12167652.
^Harrington C, Rickard J, Horsley D (July 2008). "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. 4 (4): T120-21. doi:10.1016/j.jalz.2008.05.259.
^Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D (July 2008). "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. 372 (9634): 207-15. doi:10.1016/S0140-6736(08)61074-0. PMID18640457.
^Morley, John E.; Armbrecht, Harvey James; Farr, Susan A.; Kumar, Vijaya B. (May 2012). "The senescence accelerated mouse (SAMP8) as a model for oxidative stress and Alzheimer's disease". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1822 (5): 650-656. doi:10.1016/j.bbadis.2011.11.015. ISSN0925-4439. PMID22142563.
^Wozniak MA, Mee AP, Itzhaki RF (January 2009). "Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques". The Journal of Pathology (Original study). 217 (1): 131-38. doi:10.1002/path.2449. PMID18973185.
^Dougall NJ, Bruggink S, Ebmeier KP (2004). "Systematic review of the diagnostic accuracy of 99mTc-HMPAO-SPECT in dementia". The American Journal of Geriatric Psychiatry. 12 (6): 554-70. doi:10.1176/appi.ajgp.12.6.554. PMID15545324.
^Carpenter AP, Pontecorvo MJ, Hefti FF, Skovronsky DM (August 2009). "The use of the exploratory IND in the evaluation and development of 18F-PET radiopharmaceuticals for amyloid imaging in the brain: a review of one company's experience". The Quarterly Journal of Nuclear Medicine and Molecular Imaging. 53 (4): 387-93. PMID19834448.
Irvine K, Laws KR, Gale TM, Kondel TK (2012). "Greater cognitive deterioration in women than men with Alzheimer's disease: a meta analysis". Journal of Clinical and Experimental Neuropsychology (Meta-analysis). 34 (9): 989-98. doi:10.1080/13803395.2012.712676. PMID22913619.
Harilal, Seetha; Jose, Jobin; Parambi, Della Grace Thomas; Kumar, Rajesh; Mathew, Githa Elizabeth; Uddin, Md. Sahab; Kim, Hoon; Mathew, Bijo (15 July 2019). "Advancements in nanotherapeutics for Alzheimer's disease: current perspectives". Journal of Pharmacy and Pharmacology. 71 (9): 1370-1383. doi:10.1111/jphp.13132. PMID31304982.