Jump to content

Alzheimer's disease

Edit links
Listen to this article
From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by 68.88.4.78 (talk) at 21:22, 14 May 2009 (Simplified grammar.). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

"Alzheimer" redirects here. For other uses, see Alzheimer (disambiguation).
Alzheimer's disease
SpecialtyNeurology Edit this on Wikidata
Frequency5.05% (Europe)

Alzheimer's disease (AD), also called Alzheimer disease, Senile Dementia of the Alzheimer Type (SDAT) or simply Alzheimer's, is the most common form of dementia. This incurable, degenerative, and terminal disease was first described by German psychiatrist Alois Alzheimer in 1906 and was named after him.[1] Generally it is diagnosed in people over 65 years of age,[2] although the less-prevalent early-onset Alzheimer's can occur much earlier. An estimated 26.6 million people worldwide had Alzheimer's in 2006; this number may quadruple by 2050.[3]

Although each sufferer experiences Alzheimer's in a unique way, there are many common symptoms.[4] The earliest observable symptoms are often mistakenly thought to be 'age-related' concerns, or manifestations of stress.[5] In the early stages, the most commonly recognised symptom is memory loss, such as difficulty in remembering recently learned facts. When a doctor or physician has been notified, and AD is suspected, the diagnosis is usually confirmed with behavioural assessments and cognitive tests, often followed by a brain scan if available.[6] As the disease advances, symptoms include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses decline.[5][7] Gradually, bodily functions are lost, ultimately leading to death.[8] Individual prognosis is difficult to assess, as the duration of the disease varies. AD develops for an indeterminate period of time before becoming fully apparent, and it can progress undiagnosed for years. The mean life expectancy following diagnosis is approximately seven years.[9] Fewer than 3% of individuals live more than fourteen years after diagnosis.[10]

The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with plaques and tangles in the brain.[11] Currently used treatments offer a small symptomatic benefit; no treatments to delay or halt the progression of the disease are as yet available. As of 2008, more than 500 clinical trials were investigating possible treatments for AD, but it is unknown if any of them will prove successful.[12] Many measures have been suggested for the prevention of Alzheimer's disease, but their value is unproven in slowing the course and reducing the severity of the disease. Mental stimulation, exercise, and a balanced diet are often recommended, as both a possible prevention and a sensible way of managing the disease.[13]

Because AD cannot be cured and is degenerative, management of patients is essential. The role of the main caregiver is often taken by the spouse or a close relative.[14] 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.[15][16][17] In developed countries, AD is one of the most economically costly diseases to society.[18][19]

Characteristics

The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment.

Pre-dementia

The first symptoms are often mistaken as related to ageing or stress.[5] Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of AD.[20] These early symptoms can affect the most complex daily living activities.[21] The most noticeable deficit is memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.[22][23] 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.[24][25] Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease.[26][27][28] The preclinical stage of the disease has also been termed mild cognitive impairment,[29] but there is still debate on whether this term corresponds to a different diagnostic entity by itself or just a first step of the disease.[30]

Early dementia

In people with AD the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small proportion of them, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems.[31] 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.[32][33] 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 adequately communicating basic ideas.[34][35][36] While performing fine motor tasks such as writing, drawing or dressing, certain movement coordination and planning difficulties (apraxia) may be present, making sufferers appear clumsy.[37] 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.[31]

Moderate dementia

Progressive deterioration eventually hinders independence.[31] 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.[34][38] Complex motor sequences become less coordinated as time passes, reducing the ability to perform most normal daily living activities.[39] During this phase, memory problems worsen, and the person may fail to recognise close relatives.[40] Long-term memory, which was previously intact, becomes impaired,[41] and behavioural changes become more prevalent. Common neuropsychiatric manifestations are wandering, sundowning,[42] irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. Approximately 30% of patients also develop illusionary misidentifications and other delusional symptoms.[26][43] Urinary incontinence can develop.[44] These symptoms create stress for relatives and caretakers, which can be reduced by moving the person from home care to other long-term care facilities.[31][45]

Advanced dementia

During this last stage of AD, the patient is completely dependent upon caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech.[34] Despite the loss of verbal language abilities, patients can often understand and return emotional signals.[46] Although aggressiveness can still be present, extreme apathy and exhaustion are much more common results.[31] Patients will ultimately not be able to perform even the most simple tasks without assistance. Muscle mass and mobility deteriorate to the point where they are bedridden,[47] and they lose the ability to feed themselves.[48] Finally comes death, usually caused directly by some external factor such as pressure ulcers or pneumonia, not by the disease itself.[49][50]

Causes

File:TAU HIGH.JPG
Microscopy image of a neurofibrillary tangle, conformed by hyperphosphorylated tau protein

Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis, which proposes that AD is caused by reduced synthesis of the neurotransmitter acetylcholine. The cholinergic hypothesis has not maintained widespread support, largely because medications intended to treat acetylcholine deficiency have not been very effective. Other cholinergic effects have also been proposed, for example, initiation of large-scale aggregation of amyloid,[51] leading to generalised neuroinflammation.[52]

In 1991, the amyloid hypothesis postulates that amyloid beta (Aβ) deposits are the fundamental cause of the disease.[53][54] It is a compelling theory because the gene for the amyloid beta precursor protein (APP) is located on chromosome 21, and people with trisomy 21 (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD by 40 years of age.[55][56] Also APOE4, the major genetic risk factor for AD, leads to excess amyloid buildup in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.[57] 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.[58] An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.[59]

Deposition of amyloid plaques does not correlate well with neuron loss.[60] This observation supports the tau hypothesis, the idea that tau protein abnormalities initiate the disease cascade.[54] In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies.[61] When this occurs, the microtubules disintegrate, collapsing the neuron's transport system.[62] This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.[63] Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the apoE gene.[64]

Pathophysiology

Main article: Biochemistry of Alzheimer's disease
Histopathologic image of senile plaques seen in the cerebral cortex of a person with Alzheimer's disease of presenile onset. Silver impregnation.

Neuropathology

Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.[52]

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD.[11] Plaques are dense, mostly insoluble deposits of amyloid-beta protein 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 AD patients have a greater number of them in specific brain regions such as the temporal lobe.[65]

Biochemistry

Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD.

Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain.[66] Plaques are made up of small peptides, 39–43 amino acids in length, called beta-amyloid (also written as A-beta or Aβ). Beta-amyloid is a fragment from a larger protein called amyloid precursor protein (APP), a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair.[67][68] In Alzheimer's disease, an unknown process causes APP to be divided into smaller fragments by enzymes through proteolysis.[69] One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile plaques.[11][70]

In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.

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.[71]

Disease mechanism

Exactly how disturbances of production and aggregation of the beta amyloid peptide gives rise to the pathology of AD is not known.[72] The amyloid hypothesis traditionally points to the accumulation of beta amyloid peptides as the central event triggering neuron degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces programmed cell death (apoptosis).[73] 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.[74]

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.[75]

Genetics

While the rare, early-onset form of Alzheimer's disease is mainly explained by mutations in three genes, the most common form has yet to be explained by a purely genetic model. The APOE gene is the strongest genetic risk factor for Alzheimer's discovered so far, but its presence is far from explaining all occurrences of the disease.[76]

Less than 10% of AD cases occurring before 60 years of age are due to autosomal dominant (familial) mutations, which therefore represent less than 0.01% of all cases.[76][77][78] These mutations have been discovered in three different genes: amyloid precursor protein (APP) and presenilins 1 and 2.[76] Most mutations in the APP and presenilin genes increase the production of a small protein called Abeta42, which is the main component of senile plaques.[79]

Most cases of Alzheimer's disease do not exhibit familial inheritance, but genes may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE). This gene is implicated in up to 50% of late-onset sporadic Alzheimer's cases.[80] Geneticists agree that numerous other genes also act as risk factors or have protective effects that influence the development of late onset Alzheimer's disease.[76] Over 400 genes have been tested for association with late-onset sporadic AD.[76] One example is a variant of the reelin gene that may contribute to Alzheimer's risk in women.[81]

Diagnosis

PET scan of the brain of a person with AD showing a loss of function in the temporal lobe

Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.[82][83] Advanced medical imaging with computed tomography (CT) or magnetic resonance imaging (MRI), and with single photon emission computed tomography (SPECT) or positron emission tomography (PET) can be used to help exclude other cerebral pathology or subtypes of dementia.[84] Assessment of intellectual functioning including memory testing can further characterise the state of the disease.[5] Medical organisations have created diagnostic criteria to ease and standardise the diagnostic process for practicing physicians. Sometimes the diagnosis can be confirmed or made at post-mortem when brain material is available and can be examined histologically.[85]

Diagnostic criteria

The National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) established the most commonly used diagnostic criteria for Alzheimer's disease.[86] These criteria require that the presence of cognitive impairment, and a suspected dementia syndrome, be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD. A histopathologic confirmation including a microscopic examination of brain tissue is required for a definitive diagnosis. Good statistical reliability and validity have been shown between the diagnostic criteria and definitive histopathological confirmation.[87] Eight cognitive domains are most commonly impaired in AD—memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities. These domains are equivalent to the NINCDS-ADRDA Alzheimer's Criteria as listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) published by the American Psychiatric Association.[88][89]

Diagnostic tools

Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.

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.[90][91] Neurological examination in early AD will usually provide normal results, except for obvious cognitive impairment, which may not differ from standard dementia. Further neurological examinations are crucial in the differential diagnosis of AD and other diseases.[5] 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.[92] A caregiver's viewpoint is particularly important, since a person with AD is commonly unaware of his own deficits.[93] Many times, families also have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.[94] 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[5]—causes which may, in rare cases, be reversible.[95] Psychological tests for depression are employed, since depression can either be concurrent with AD or be the cause of cognitive impairment.[96][97]

When available as a diagnostic tool, SPECT and PET neuroimaging are used to confirm a diagnosis of Alzheimer's in conjunction with evaluations involving mental status examination.[98]In a person already having dementia, SPECT appears to be superior in differentiating Alzheimer's disease from other possible causes, compared with the usual attempts employing mental testing and medical history analysis.[99] A new technique known as PiB PET has been developed for directly and clearly imaging beta-amyloid deposits in vivo using a tracer that binds selectively to the Abeta deposits.[100] Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins.[101] Both advances have led to the proposal of new diagnostic criteria.[5][86]

Prevention

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.

Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results. At present, there is no definitive evidence to support that any particular measure is effective in preventing AD.[102] However, 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, in fact, these factors can help to prevent AD.[103]

The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease.[104] Several vitamins such as B12, B3, C or folic acid have been found in some studies to be related to a reduced risk of AD[105] but other studies indicate that they do not have any significant effect on the onset or course of the disease and may have important adverse effects.[106] Curcumin from the curry spice turmeric has shown some effectiveness in preventing brain damage in mouse models.[107]

Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,[108][109] statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease.[110][111] However long-term usage of non-steroidal anti-inflammatory drug (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals.[112][113] Other pharmaceutical therapies such as female hormone replacement therapy are no longer thought to prevent dementia.[114][115] A 2007 systematic review concluded that there was inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment,[116] and a recent study concludes that it has no effect in reducing the rate of AD incidence.[117]

Intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instruments, or regular social interaction may also delay the onset or reduce the severity of Alzheimer's disease.[118][119] Bilingualism is also related to a later onset of Alzheimer's.[120]

Some studies have shown an increased risk of developing AD with occupational exposure to magnetic fields,[121][122] intake of metals, particularly aluminium,[123][124] or exposure to solvents.[125] The quality of some of these studies has been criticised,[126] and other studies have concluded that there is no relationship between these environmental factors and the development of AD.[127][128][129][130]

Management

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.

Pharmaceutical

Three-dimensional molecular model of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms
Molecular structure of memantine, a medication approved for advanced AD symptoms

Four medications are currently approved by regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) to treat the cognitive manifestations of AD: three are acetylcholinesterase inhibitors and the other is memantine, an NMDA receptor antagonist. No drug has an indication for delaying or halting the progression of the disease.

Reduction in the activity of the cholinergic neurons is a well-known feature of Alzheimer's disease.[131] 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.[132] As of 2008, the cholinesterase inhibitors approved for the management of AD symptoms are donepezil (brand name Aricept),[133] galantamine (Razadyne),[134] and rivastigmine (branded as Exelon[135] and Exelon Patch[136]). There is evidence for the efficacy of these medications in mild to moderate Alzheimer’s disease,[137] and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia.[138] The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD.[139] 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.[140]

Glutamate is a useful excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis.[141] Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda),[142] is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA receptors and inhibiting their overstimulation by glutamate.[141] Memantine has been shown to be moderately efficacious in the treatment of moderate to severe Alzheimer’s disease. Its effects in the initial stages of AD are unknown.[143] Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue.[144] The combination of memantine and donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".[145]

Antipsychotic drugs are modestly useful in reducing aggression and psychosis in Alzheimer's patients with behavioural problems, but are associated with serious adverse effects, such as cerebrovascular events, movement difficulties or cognitive decline, that do not permit their routine use.[146][147] When used in the long-term, they have been shown to associate with increased mortality.[147]

Psychosocial intervention

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.[148]

Behavioural interventions attempt to identify and reduce the antecedents and consequences of problem behaviours. This approach has not shown success in improving overall functioning,[149] but can help to reduce some specific problem behaviours, such as incontinence.[150] There is a lack of high quality data on the effectiveness of these techniques in other behaviour problems such as wandering.[151][152]

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 patients adjust to their illness.[148] 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.[153] 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 preliminary evidence indicating that SPT may reduce anxiety and challenging behaviours.[154][155] 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 little evidence to support the usefulness of these therapies.[156][157]

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 in order 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,[158][159] although in some studies these effects were transient and negative effects, such as frustration, have also been reported.[148]

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.[148]

Caregiving

Further information: [[:Caregiving and dementia]]

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.[160][161] 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.[148][162][163] The patient may also become incapable of feeding themselves, so they require food in smaller pieces or pureed.[164] 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.[165][166] 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.[148]

As the disease progresses, different medical issues can appear, such as oral and dental disease, pressure ulcers, malnutrition, hygiene problems, or respiratory, skin, or eye infections. Careful management can prevent them, while professional treatment is needed when they do arise.[50][167] During the final stages of the disease, treatment is centred on relieving discomfort until death.[168]

Prognosis

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. He 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.[31]

Life expectancy of the population with the disease is reduced.[9][169][170] The mean life expectancy following diagnosis is approximately seven years.[9] Fewer than 3% of patients live more than fourteen years.[10] 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.[169][171][172] 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.[170] Men have a less favourable survival prognosis than women.[10][173]

The disease is the underlying cause of death in 70% of all cases.[9] 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.[9][173]

Epidemiology

AD incidence rates
after 65 years of age[174]
Age Incidence
(new affected)
per thousand
person–years
65–69  3
70–74  6
75–79  9
80–84 23
85–89 40
90–   69

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 a given time.

Regarding incidence, cohort longitudinal studies (studies where a disease-free population is followed over the years) provide rates between 10–15 per thousand person–years for all dementias and 5–8 for AD,[174][175] 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.[174][175] There are also sex differences in the incidence rates, women having a higher risk of developing AD particularly in the population older than 85.[175][176]

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 the year 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.[177] Prevalence rates in less developed regions are lower.[178] 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.[179] Other studies have reached similar conclusions.[178] 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 the year 2050.[3]

History

Alois Alzheimer's patient Auguste D in 1902. Hers was the first described case of what became known as Alzheimer's diease.

The ancient Greek and Roman philosophers and physicians associated old age with increasing dementia.[1] It was not until 1901 that German psychiatrist Alois Alzheimer identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called Auguste D. Alzheimer followed her until she died in 1906, when he first reported the case publicly.[180] During the next five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease.[1] The disease was first described as a distinctive disease by Emil Kraepelin, who included Alzheimer’s disease, also named presenile dementia by Kraepelin, as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published in 1910.[181]

For most of the twentieth 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 of different aetiologies.[182] This eventually led to the diagnosis of Alzheimer's disease independently of age.[183] 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.[184]

Society and culture

Social costs

Dementia, and specifically Alzheimer's disease, may be among the most costly diseases for society in Europe and the United States,[18][19] while their cost in other countries such as Argentina,[185] or South Korea,[186] 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 nursing home care, direct nonmedical costs such as in-home day care, and indirect costs such as lost productivity of both patient and caregiver.[19] Numbers vary between studies but dementia costs worldwide have been calculated around $160 billion,[187] while costs of Alzheimer in the United States may be $100 billion each year.[19]

The greatest origin of costs for society is the long-term care by health care professionals and particularly institutionalisation, which corresponds to 2/3 of the total costs for society.[18] The cost of living at home is also very high,[18] especially when informal costs for the family, such as caregiving time and caregiver's lost earnings, are taken into account.[188]

Costs increase with dementia severity and the presence of behavioural disturbances,[189] and are related to the increased caregiving time required for the provision of physical care.[188] 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.[19]

Caregiving burden

Further information: [[:Caregiving and dementia]]

The role of the main caregiver is often taken by the spouse or a close relative.[14] Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical or economic aspects.[15][16][17] Home care is usually preferred by patients and families.[190] This option also delays or eliminates the need for more professional and costly levels of care.[190][191] Nevertheless two-thirds of nursing home residents have dementias.[148]

Dementia caregivers are subject to high rates of physical and mental disorders.[192] 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.[193][194] 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.[188][195]

Cognitive behavioural therapy and the teaching of coping strategies either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.[15][196]

Notable cases

Further information: [[:Alzheimer's in the media]]
Charlton Heston and Ronald Reagan at a meeting in the White House. Both of them would later develop Alzheimer's disease.

As Alzheimer's disease is highly prevalent, many notable people have developed it. Well-known examples are former United States President Ronald Reagan and Irish writer Iris Murdoch, both of whom were the subjects of scientific articles examining how their cognitive capacities deteriorated with the disease.[197][198][199] Other notable cases include the retired footballer Ferenc Puskas,[200] the former Prime Ministers Harold Wilson (Great Britain) and Adolfo Suárez (Spain),[201][202] the actress Rita Hayworth,[203] the actor Charlton Heston,[204] and the novelist Terry Pratchett.[205]

AD has also been portrayed in films such as: Iris (2001),[206] based on John Bayley's memoir of his wife Iris Murdoch;[207] The Notebook (2004),[208] based on Nicholas Sparks' 1996 novel of the same name;[209] Thanmathra (2005);[210] Memories of Tomorrow (Ashita no Kioku) (2006),[211] based on Hiroshi Ogiwara's novel of the same name;[212] and Away from Her (2006), based on Alice Munro's short story "The Bear Came over the Mountain".[213] Documentaries on Alzheimer's disease include Malcolm and Barbara: A Love Story (1999) and Malcolm and Barbara: Love’s Farewell (2007), both featuring Malcolm Pointon.[214]

Research directions

Main article: Alzheimer's disease clinical research

As of 2008, the safety and efficacy of more than 400 pharmaceutical treatments are being investigated in clinical trials worldwide, and approximately one-fourth of these compounds are in Phase III trials, which is the last step prior to review by regulatory agencies.[215]

One area of clinical research is focused on treating the underlying disease pathology. Reduction of amyloid beta levels is a common target of compounds [216] 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.[217] An example of such a vaccine under investigation was ACC-001,[218][219] although the trials were suspended in 2008.[220] Another similar agent is bapineuzumab, an antibody designed as identical to the naturally induced anti-amyloid antibody. [221] Other approaches are neuroprotective agents, such as AL-108,[222] and metal-protein interaction attenuation agents, such as PBT2.[223] A TNFα receptor fusion protein, etanercept has showed encouraging results.[224]

In 2008, two separate clinical trials showed positive results in modifying the course of disease in mild to moderate AD with methylthioninium chloride (trade name rember), a drug that inhibits tau aggregation,[225][226] and dimebon, an antihistamine.[227]

References

  1. ^ a b c Berchtold NC, Cotman CW (1998). "Evolution in the conceptualization of dementia and Alzheimer's disease: Greco-Roman period to the 1960s". Neurobiol. Aging. 19 (3): 173–89. doi:10.1016/S0197-4580(98)00052-9. PMID 9661992. Cite error: The named reference "pmid9661992" was defined multiple times with different content (see the help page).
  2. ^ Brookmeyer R, Gray S, Kawas C (1998). "Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset". Am J Public Health. 88 (9): 1337–42. doi:10.2105/AJPH.88.9.1337. PMC 1509089. PMID 9736873. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ a b 2006 prevalence estimate:
  4. ^ "What is Alzheimer's disease?". Alzheimers.org.uk. 2007. Retrieved 2008-02-21. {{cite web}}: Unknown parameter |month= ignored (help)
  5. ^ a b c d e f g Waldemar G, Dubois B, Emre M; et al. (2007). "Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline". Eur. J. Neurol. 14 (1): e1–26. doi:10.1111/j.1468-1331.2006.01605.x. PMID 17222085. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ "Alzheimer's diagnosis of AD". Alzheimer's Research Trust. Retrieved 2008-02-29.
  7. ^ Tabert MH, Liu X, Doty RL, Serby M, Zamora D, Pelton GH, Marder K, Albers MW, Stern Y, Devanand DP (2005). "A 10-item smell identification scale related to risk for Alzheimer's disease". Ann. Neurol. 58 (1): 155–160. doi:10.1002/ana.20533. PMID 15984022.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ "Understanding stages and symptoms of Alzheimer's disease". National Institute on Aging. 2007-10-26. Retrieved 2008-02-21.
  9. ^ a b c d e Mölsä PK, Marttila RJ, Rinne UK (1986). "Survival and cause of death in Alzheimer's disease and multi-infarct dementia". Acta Neurol. Scand. 74 (2): 103–7. doi:10.1111/j.1600-0404.1986.tb04634.x. PMID 3776457. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ a b c Mölsä PK, Marttila RJ, Rinne UK (1995). "Long-term survival and predictors of mortality in Alzheimer's disease and multi-infarct dementia". Acta Neurol. Scand. 91 (3): 159–64. PMID 7793228. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ a b c Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J (2004). "The importance of neuritic plaques and tangles to the development and evolution of AD". Neurology. 62 (11): 1984–9. PMID 15184601. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ "Alzheimer's Disease Clinical Trials". US National Institutes of Health. Retrieved 2008-08-18.
  13. ^ "Can Alzheimer's disease be prevented" (pdf). National Institute on Aging. 2006-08-29. Retrieved 2008-02-29.
  14. ^ a b "The MetLife study of Alzheimer's disease: The caregiving experience" (PDF). MetLife Mature Market Institute. 2006. Retrieved 2008-02-12. {{cite web}}: Unknown parameter |month= ignored (help)
  15. ^ a b c Thompson CA, Spilsbury K, Hall J, Birks Y, Barnes C, Adamson J (2007). "Systematic review of information and support interventions for caregivers of people with dementia". BMC Geriatr. 7: 18. doi:10.1186/1471-2318-7-18. PMC 1951962. PMID 17662119.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  16. ^ a b Schneider J, Murray J, Banerjee S, Mann A (1999). "EUROCARE: a cross-national study of co-resident spouse carers for people with Alzheimer's disease: I—Factors associated with carer burden". International Journal of Geriatric Psychiatry. 14 (8): 651–661. doi:10.1002/(SICI)1099-1166(199908)14:8<651::AID-GPS992>3.0.CO;2-B. PMID 10489656. {{cite journal}}: |access-date= requires |url= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ a b Murray J, Schneider J, Banerjee S, Mann A (1999). "EUROCARE: a cross-national study of co-resident spouse carers for people with Alzheimer's disease: II--A qualitative analysis of the experience of caregiving". International Journal of Geriatric Psychiatry. 14 (8): 662–667. doi:10.1002/(SICI)1099-1166(199908)14:8<662::AID-GPS993>3.0.CO;2-4. PMID 10489657. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid10489657" was defined multiple times with different content (see the help page).
  18. ^ a b c d Bonin-Guillaume S, Zekry D, Giacobini E, Gold G, Michel JP (2005). "Impact économique de la démence (English: The economical impact of dementia)". Presse Med (in French). 34 (1): 35–41. ISSN 0755-4982. PMID 15685097. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ a b c d e Meek PD, McKeithan K, Schumock GT (1998). "Economic considerations in Alzheimer's disease". Pharmacotherapy. 18 (2 Pt 2): 68–73, discussion 79–82. PMID 9543467.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ Preclinical:
  21. ^ Perneczky R, Pohl C, Sorg C, Hartmann J, Komossa K, Alexopoulos P, Wagenpfeil S, Kurz A (2006). "Complex activities of daily living in mild cognitive impairment: conceptual and diagnostic issues". Age Ageing. 35 (3): 240–245. doi:10.1093/ageing/afj054. PMID 16513677.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ Arnáiz E, Almkvist O (2003). "Neuropsychological features of mild cognitive impairment and preclinical Alzheimer's disease". Acta Neurol. Scand., Suppl. 179: 34–41. doi:10.1034/j.1600-0404.107.s179.7.x. PMID 12603249. {{cite journal}}: |access-date= requires |url= (help)
  23. ^ Kazui H, Matsuda A, Hirono N; et al. (2005). "Everyday memory impairment of patients with mild cognitive impairment". Dement Geriatr Cogn Disord. 19 (5–6): 331–7. doi:10.1159/000084559. PMID 15785034. Retrieved 2008-06-12. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  24. ^ Rapp MA, Reischies FM (2005). "Attention and executive control predict Alzheimer disease in late life: results from the Berlin Aging Study (BASE)". American Journal of Geriatric Psychiatry. 13 (2): 134–141. doi:10.1176/appi.ajgp.13.2.134. PMID 15703322.
  25. ^ Spaan PE, Raaijmakers JG, Jonker C (2003). "Alzheimer's disease versus normal ageing: a review of the efficiency of clinical and experimental memory measures". Journal of Clinical Experimental Neuropsychology. 25 (2): 216–233. doi:10.1076/jcen.25.2.216.13638. PMID 12754679.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  26. ^ a b Craig D, Mirakhur A, Hart DJ, McIlroy SP, Passmore AP (2005). "A cross-sectional study of neuropsychiatric symptoms in 435 patients with Alzheimer's disease". American Journal of Geriatric Psychiatry. 13 (6): 460–468. doi:10.1176/appi.ajgp.13.6.460. PMID 15956265.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ^ Robert PH, Berr C, Volteau M, Bertogliati C, Benoit M, Sarazin M, Legrain S, Dubois B (2006). "Apathy in patients with mild cognitive impairment and the risk of developing dementia of Alzheimer's disease: a one-year follow-up study". Clin Neurol Neurosurg. 108 (8): 733–736. doi:10.1016/j.clineuro.2006.02.003. PMID 16567037.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ^ Palmer K, Berger AK, Monastero R, Winblad B, Bäckman L, Fratiglioni L (2007). "Predictors of progression from mild cognitive impairment to Alzheimer disease". Neurology. 68 (19): 1596–1602. doi:10.1212/01.wnl.0000260968.92345.3f. PMID 17485646.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ Small BJ, Gagnon E, Robinson B (2007). "Early identification of cognitive deficits: preclinical Alzheimer's disease and mild cognitive impairment". Geriatrics. 62 (4): 19–23. PMID 17408315. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  30. ^ Petersen RC (2007). "The current status of mild cognitive impairment—what do we tell our patients?". Nat Clin Pract Neurol. 3 (2): 60–1. doi:10.1038/ncpneuro0402. PMID 17279076. {{cite journal}}: Unknown parameter |month= ignored (help)
  31. ^ a b c d e f Förstl H, Kurz A (1999). "Clinical features of Alzheimer's disease". European Archives of Psychiatry and Clinical Neuroscience. 249 (6): 288–290. doi:10.1007/s004060050101. PMID 10653284.
  32. ^ Carlesimo GA, Oscar-Berman M (1992). "Memory deficits in Alzheimer's patients: a comprehensive review". Neuropsychol Rev. 3 (2): 119–69. doi:10.1007/BF01108841. PMID 1300219. {{cite journal}}: Unknown parameter |month= ignored (help)
  33. ^ Jelicic M, Bonebakker AE, Bonke B (1995). "Implicit memory performance of patients with Alzheimer's disease: a brief review". International Psychogeriatrics. 7 (3): 385–392. doi:10.1017/S1041610295002134. PMID 8821346.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  34. ^ a b c Frank EM (1994). "Effect of Alzheimer's disease on communication function". J S C Med Assoc. 90 (9): 417–23. PMID 7967534. {{cite journal}}: Unknown parameter |month= ignored (help)
  35. ^ Becker JT, Overman AA (2002). "[The semantic memory deficit in Alzheimer's disease]". Rev Neurol (in Spanish; Castilian). 35 (8): 777–83. PMID 12402233.{{cite journal}}: CS1 maint: unrecognized language (link)
  36. ^ Hodges JR, Patterson K (1995). "Is semantic memory consistently impaired early in the course of Alzheimer's disease? Neuroanatomical and diagnostic implications". Neuropsychologia. 33 (4): 441–59. doi:10.1016/0028-3932(94)00127-B. PMID 7617154. {{cite journal}}: Unknown parameter |month= ignored (help)
  37. ^ Benke T (1993). "Two forms of apraxia in Alzheimer's disease". Cortex. 29 (4): 715–25. PMID 8124945. {{cite journal}}: Unknown parameter |month= ignored (help)
  38. ^ Forbes KE, Shanks MF, Venneri A (2004). "The evolution of dysgraphia in Alzheimer's disease". Brain Res. Bull. 63 (1): 19–24. doi:10.1016/j.brainresbull.2003.11.005. PMID 15121235. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  39. ^ Galasko D, Schmitt F, Thomas R, Jin S, Bennett D (2005). "Detailed assessment of activities of daily living in moderate to severe Alzheimer's disease". Journal of the International Neuropsychology Society. 11 (4): 446–453. PMID 16209425.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  40. ^ Galasko D, Schmitt F, Thomas R, Jin S, Bennett D (2005). "Detailed assessment of activities of daily living in moderate to severe Alzheimer's disease". J Int Neuropsychol Soc. 11 (4): 446–53. PMID 16209425. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  41. ^ Sartori G, Snitz BE, Sorcinelli L, Daum I (2004). "Remote memory in advanced Alzheimer's disease". Arch Clin Neuropsychol. 19 (6): 779–89. doi:10.1016/j.acn.2003.09.007. PMID 15288331. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  42. ^ Volicer L, Harper DG, Manning BC, Goldstein R, Satlin A (2001). "Sundowning and circadian rhythms in Alzheimer's disease". Am J Psychiatry. 158 (5): 704–11. doi:10.1176/appi.ajp.158.5.704. PMID 11329390. Retrieved 2008-08-27. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  43. ^ Neuropsychiatric symptoms:
    • Scarmeas N, Brandt J, Blacker D; et al. (2007). "Disruptive behavior as a predictor in Alzheimer disease". Arch. Neurol. 64 (12): 1755–61. doi:10.1001/archneur.64.12.1755. PMID 18071039. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
    • Tatsch MF, Bottino CM, Azevedo D; et al. (2006). "Neuropsychiatric symptoms in Alzheimer disease and cognitively impaired, nondemented elderly from a community-based sample in Brazil: prevalence and relationship with dementia severity". Am J Geriatr Psychiatry. 14 (5): 438–45. doi:10.1097/01.JGP.0000218218.47279.db. PMID 16670248. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
    • Volicer L, Bass EA, Luther SL (2007). "Agitation and resistiveness to care are two separate behavioral syndromes of dementia". J Am Med Dir Assoc. 8 (8): 527–32. doi:10.1016/j.jamda.2007.05.005. PMID 17931577. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  44. ^ Honig LS, Mayeux R (2001). "Natural history of Alzheimer's disease". Aging (Milano). 13 (3): 171–82. PMID 11442300. {{cite journal}}: Unknown parameter |month= ignored (help)
  45. ^ Gold DP, Reis MF, Markiewicz D, Andres D (1995). "When home caregiving ends: a longitudinal study of outcomes for caregivers of relatives with dementia". J Am Geriatr Soc. 43 (1): 10–6. PMID 7806732. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  46. ^ Bär M, Kruse A, Re S (2003). "[Situations of emotional significance in residents suffering from dementia]". Z Gerontol Geriatr (in German). 36 (6): 454–62. doi:10.1007/s00391-003-0191-0. PMID 14685735. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  47. ^ Souren LE, Franssen EH, Reisberg B (1995). "Contractures and loss of function in patients with Alzheimer's disease". J Am Geriatr Soc. 43 (6): 650–5. PMID 7775724. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  48. ^ Berkhout AM, Cools HJ, van Houwelingen HC (1998). "The relationship between difficulties in feeding oneself and loss of weight in nursing-home patients with dementia". Age Ageing. 27 (5): 637–41. doi:10.1093/ageing/27.5.637. PMID 12675103. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  49. ^ Wada H, Nakajoh K, Satoh-Nakagawa T; et al. (2001). "Risk factors of aspiration pneumonia in Alzheimer's disease patients". Gerontology. 47 (5): 271–6. doi:10.1159/000052811. PMID 11490146. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  50. ^ a b Gambassi G, Landi F, Lapane KL, Sgadari A, Mor V, Bernabei R (1999). "Predictors of mortality in patients with Alzheimer's disease living in nursing homes". J. Neurol. Neurosurg. Psychiatr. 67 (1): 59–65. doi:10.1136/jnnp.67.1.59. PMC 1736445. PMID 10369823. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  51. ^ Shen ZX (2004). "Brain cholinesterases: II. The molecular and cellular basis of Alzheimer's disease". Med Hypotheses. 63 (2): 308–21. doi:10.1016/j.mehy.2004.02.031. PMID 15236795.
  52. ^ a b Wenk GL (2003). "Neuropathologic changes in Alzheimer's disease". J Clin Psychiatry. 64 Suppl 9: 7–10. PMID 12934968.
  53. ^ Hardy J, Allsop D (1991). "Amyloid deposition as the central event in the aetiology of Alzheimer's disease". Trends Pharmacol. Sci. 12 (10): 383–88. doi:10.1016/0165-6147(91)90609-V. PMID 1763432. {{cite journal}}: Unknown parameter |month= ignored (help)
  54. ^ a b Mudher A, Lovestone S (2002). "Alzheimer's disease-do tauists and baptists finally shake hands?". Trends Neurosci. 25 (1): 22–26. doi:10.1016/S0166-2236(00)02031-2. PMID 11801334. {{cite journal}}: Unknown parameter |month= ignored (help)
  55. ^ Nistor M, Don M, Parekh M; et al. (2007). "Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain". Neurobiol Aging. 28 (10): 1493–1506. doi:10.1016/j.neurobiolaging.2006.06.023. PMID 16904243. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  56. ^ Lott IT, Head E (2005). "Alzheimer disease and Down syndrome: factors in pathogenesis". Neurobiol Aging. 26 (3): 383–89. doi:10.1016/j.neurobiolaging.2004.08.005. PMID 15639317. {{cite journal}}: Unknown parameter |month= ignored (help)
  57. ^ Polvikoski T, Sulkava R, Haltia M; et al. (1995). "Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein". N Engl J Med. 333 (19): 1242–47. doi:10.1056/NEJM199511093331902. PMID 7566000. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  58. ^ Transgenic mice:
    • Games D, Adams D, Alessandrini R; et al. (1995). "Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein". Nature. 373 (6514): 523–27. doi:10.1038/373523a0. PMID 7845465. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
    • Masliah E, Sisk A, Mallory M, Mucke L, Schenk D, Games D (1996). "Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer's disease". J Neurosci. 16 (18): 5795–811. PMID 8795633. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
    • Hsiao K, Chapman P, Nilsen S; et al. (1996). "Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice". Science (journal). 274 (5284): 99–102. doi:10.1126/science.274.5284.99. PMID 8810256. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
    • Lalonde R, Dumont M, Staufenbiel M, Sturchler-Pierrat C, Strazielle C. (2002). "Spatial learning, exploration, anxiety, and motor coordination in female APP23 transgenic mice with the Swedish mutation". Brain Research (journal). 956: 36–44, year=2002. doi:10.1016/S0006-8993(02)03476-5. PMID 12426044.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  59. ^ Holmes C, Boche D, Wilkinson D; et al. (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. PMID 18640458. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  60. ^ Schmitz C, Rutten BP, Pielen A; et al. (2004). "Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease". Am J Pathol. 164 (4): 1495–1502. PMC 1615337. PMID 15039236. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  61. ^ Goedert M, Spillantini MG, Crowther RA (1991). "Tau proteins and neurofibrillary degeneration". Brain Pathol. 1 (4): 279–86. doi:10.1111/j.1750-3639.1991.tb00671.x. PMID 1669718. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  62. ^ Iqbal K, Alonso Adel C, Chen S; et al. (2005). "Tau pathology in Alzheimer disease and other tauopathies". Biochim Biophys Acta. 1739 (2–3): 198–210. doi:10.1016/j.bbadis.2004.09.008. PMID 15615638. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  63. ^ Chun W, Johnson GV (2007). "The role of tau phosphorylation and cleavage in neuronal cell death". Front Biosci. 12: 733–56. doi:10.2741/2097. PMID 17127334.
  64. ^ Itzhaki RF, Wozniak MA (2008). "Herpes simplex virus type 1 in Alzheimer's disease: the enemy within". J Alzheimers Dis. 13 (4): 393–405. ISSN 1387-2877. PMID 18487848. {{cite journal}}: Unknown parameter |month= ignored (help)
  65. ^ Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH (1994). "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". Cereb. Cortex. 4 (2): 138–50. doi:10.1093/cercor/4.2.138. PMID 8038565.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  66. ^ 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 Med. 4 (1–2): 21–36. doi:10.1385/NMM:4:1-2:21. PMID 14528050.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  67. ^ Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J (2006). "Synapse formation and function is modulated by the amyloid precursor protein". J. Neurosci. 26 (27): 7212–21. doi:10.1523/JNEUROSCI.1450-06.2006. PMID 16822978. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  68. ^ Turner PR, O'Connor K, Tate WP, Abraham WC (2003). "Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory". Prog. Neurobiol. 70 (1): 1–32. doi:10.1016/S0301-0082(03)00089-3. PMID 12927332. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  69. ^ Hooper NM (2005). "Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein". Biochem. Soc. Trans. 33 (Pt 2): 335–8. doi:10.1042/BST0330335. PMID 15787600. {{cite journal}}: Unknown parameter |month= ignored (help)
  70. ^ Ohnishi S, Takano K (2004). "Amyloid fibrils from the viewpoint of protein folding". Cell. Mol. Life Sci. 61 (5): 511–24. doi:10.1007/s00018-003-3264-8. PMID 15004691. {{cite journal}}: Unknown parameter |month= ignored (help)
  71. ^ Hernández F, Avila J (2007). "Tauopathies". Cell. Mol. Life Sci. 64 (17): 2219–33. doi:10.1007/s00018-007-7220-x. PMID 17604998. {{cite journal}}: Unknown parameter |month= ignored (help)
  72. ^ Van Broeck B, Van Broeckhoven C, Kumar-Singh S (2007). "Current insights into molecular mechanisms of Alzheimer disease and their implications for therapeutic approaches". Neurodegener Dis. 4 (5): 349–65. doi:10.1159/000105156. PMID 17622778.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  73. ^ Yankner BA, Duffy LK, Kirschner DA (1990). "Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides". Science (journal). 250 (4978): 279–82. doi:10.1126/science.2218531. PMID 2218531. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  74. ^ Chen X, Yan SD (2006). "Mitochondrial Abeta: a potential cause of metabolic dysfunction in Alzheimer's disease". IUBMB Life. 58 (12): 686–94. doi:10.1080/15216540601047767. PMID 17424907. {{cite journal}}: Unknown parameter |month= ignored (help)
  75. ^ Greig NH, Mattson MP, Perry T; et al. (2004). "New therapeutic strategies and drug candidates for neurodegenerative diseases: p53 and TNF-alpha inhibitors, and GLP-1 receptor agonists". Ann. N. Y. Acad. Sci. 1035: 290–315. doi:10.1196/annals.1332.018. PMID 15681814. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  76. ^ a b c d e Waring SC, Rosenberg RN (2008). "Genome-wide association studies in Alzheimer disease". Arch. Neurol. 65 (3): 329–34. doi:10.1001/archneur.65.3.329. PMID 18332245. {{cite journal}}: Unknown parameter |month= ignored (help)
  77. ^ Hoenicka J (2006 March 1–15). "Genes in Alzheimer's disease". Rev Neurol. 42 (5): 302–05. PMID 16538594. {{cite journal}}: Check date values in: |date= (help)
  78. ^ Campion D, Dumanchin C, Hannequin D; et al. (1999). "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum". Am. J. Hum. Genet. 65 (3): 664–70. doi:10.1086/302553. PMC 1377972. PMID 10441572. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  79. ^ Selkoe DJ (1999). "Translating cell biology into therapeutic advances in Alzheimer's disease". Nature. 399 (6738 Suppl): A23–31. doi:10.1038/19866. PMID 10392577. {{cite journal}}: Unknown parameter |month= ignored (help)
  80. ^ Strittmatter WJ, Saunders AM, Schmechel D; et al. (1993). "Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease". Proc. Natl. Acad. Sci. USA. 90 (5): 1977–81. doi:10.1073/pnas.90.5.1977. PMC 46003. PMID 8446617. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  81. ^ Seripa D, Matera MG, Franceschi M; et al. (2008). "The RELN locus in Alzheimer's disease". J Alzheimers Dis. 14 (3): 335–44. PMID 18599960. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  82. ^ Mendez MF (2006). "The accurate diagnosis of early-onset dementia". International Journal of Psychiatry Medicine. 36 (4): 401–412. doi:10.2190/Q6J4-R143-P630-KW41. PMID 17407994.
  83. ^ Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J (2006). "Therapeutic approaches to Alzheimer's disease". Brain. 129 (Pt 11): 2840–55. doi:10.1093/brain/awl280. PMID 17018549. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  84. ^ "Dementia: Quick reference guide" (PDF). London: (UK) National Institute for Health and Clinical Excellence. 2006. ISBN 1-84629-312-X. Retrieved 2008-02-22. {{cite web}}: Unknown parameter |month= ignored (help)
  85. ^ McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (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. PMID 6610841. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  86. ^ a b Dubois B, Feldman HH, Jacova C; et al. (2007). "Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria". Lancet Neurol. 6 (8): 734–46. doi:10.1016/S1474-4422(07)70178-3. PMID 17616482. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  87. ^ Blacker D, Albert MS, Bassett SS, Go RC, Harrell LE, Folstein MF (1994). "Reliability and validity of NINCDS-ADRDA criteria for Alzheimer's disease. The National Institute of Mental Health Genetics Initiative". Arch. Neurol. 51 (12): 1198–204. PMID 7986174. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  88. ^ American Psychiatric Association (2000). Diagnostic and statistical manual of mental disorders: DSM-IV-TR (4th Edition Text Revision ed.). Washington DC: American Psychiatric Association. ISBN 0890420254.
  89. ^ Ito N (1996). "[Clinical aspects of dementia]". Hokkaido Igaku Zasshi (in Japanese). 71 (3): 315–20. PMID 8752526. {{cite journal}}: Unknown parameter |month= ignored (help)
  90. ^ Tombaugh TN, McIntyre NJ (1992). "The mini-mental state examination: a comprehensive review". J Am Geriatr Soc. 40 (9): 922–35. PMID 1512391. {{cite journal}}: Unknown parameter |month= ignored (help)
  91. ^ Pasquier F (1999). "Early diagnosis of dementia: neuropsychology". J. Neurol. 246 (1): 6–15. doi:10.1007/s004150050299. PMID 9987708. {{cite journal}}: Unknown parameter |month= ignored (help)
  92. ^ Harvey PD, Moriarty PJ, Kleinman L; et al. (2005). "The validation of a caregiver assessment of dementia: the Dementia Severity Scale". Alzheimer Dis Assoc Disord. 19 (4): 186–94. doi:10.1097/01.wad.0000189034.43203.60. PMID 16327345. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  93. ^ Antoine C, Antoine P, Guermonprez P, Frigard B (2004). "[Awareness of deficits and anosognosia in Alzheimer's disease.]". Encephale (in French). 30 (6): 570–7. PMID 15738860.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  94. ^ Cruz VT, Pais J, Teixeira A, Nunes B (2004). "[The initial symptoms of Alzheimer disease: caregiver perception]". Acta Med Port (in Portuguese). 17 (6): 435–44. PMID 16197855.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  95. ^ Clarfield AM (2003). "The decreasing prevalence of reversible dementias: an updated meta-analysis". Arch. Intern. Med. 163 (18): 2219–29. doi:10.1001/archinte.163.18.2219. PMID 14557220. {{cite journal}}: Unknown parameter |month= ignored (help)
  96. ^ Geldmacher DS, Whitehouse PJ (1997). "Differential diagnosis of Alzheimer's disease". Neurology. 48 (5 Suppl 6): S2–9. PMID 9153154. {{cite journal}}: Unknown parameter |month= ignored (help)
  97. ^ Potter GG, Steffens DC (2007). "Contribution of depression to cognitive impairment and dementia in older adults". Neurologist. 13 (3): 105–17. doi:10.1097/01.nrl.0000252947.15389.a9. PMID 17495754. {{cite journal}}: Unknown parameter |month= ignored (help)
  98. ^ Bonte FJ, Harris TS, Hynan LS, Bigio EH, White CL (2006). "Tc-99m HMPAO SPECT in the differential diagnosis of the dementias with histopathologic confirmation". Clin Nucl Med. 31 (7): 376–8. doi:10.1097/01.rlu.0000222736.81365.63. PMID 16785801. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  99. ^ Dougall NJ, Bruggink S, Ebmeier KP (2004). "Systematic review of the diagnostic accuracy of 99mTc-HMPAO-SPECT in dementia". Am J Geriatr Psychiatry. 12 (6): 554–70. doi:10.1176/appi.ajgp.12.6.554. PMID 15545324.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  100. ^ PiB PET:
  101. ^ Marksteiner J, Hinterhuber H, Humpel C (2007). "Cerebrospinal fluid biomarkers for diagnosis of Alzheimer's disease: beta-amyloid(1-42), tau, phospho-tau-181 and total protein". Drugs Today. 43 (6): 423–31. doi:10.1358/dot.2007.43.6.1067341. PMID 17612711. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  102. ^ Prevention recommendations not supported:
  103. ^ Szekely CA, Breitner JC, Zandi PP (2007). "Prevention of Alzheimer's disease". Int Rev Psychiatry. 19 (6): 693–706. doi:10.1080/09540260701797944. PMID 18092245.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  104. ^ Mediterranean diet:
  105. ^ Vitamins prevent:
  106. ^ Vitamins do not prevent:
    • Morris MC, Evans DA, Schneider JA, Tangney CC, Bienias JL, Aggarwal NT (2006). "Dietary folate and vitamins B-12 and B-6 not associated with incident Alzheimer's disease". J. Alzheimers Dis. 9 (4): 435–43. PMID 16917153.{{cite journal}}: CS1 maint: multiple names: authors list (link)
    • Malouf M, Grimley EJ, Areosa SA (2003). "Folic acid with or without vitamin B12 for cognition and dementia". Cochrane Database Syst Rev (4): CD004514. doi:10.1002/14651858.CD004514. PMID 14584018.{{cite journal}}: CS1 maint: multiple names: authors list (link)
    • Sun Y, Lu CJ, Chien KL, Chen ST, Chen RC (2007). "Efficacy of multivitamin supplementation containing vitamins B6 and B12 and folic acid as adjunctive treatment with a cholinesterase inhibitor in Alzheimer's disease: a 26-week, randomised, double-blind, placebo-controlled study in Taiwanese patients". Clin Ther. 29 (10): 2204–14. doi:10.1016/j.clinthera.2007.10.012. PMID 18042476.{{cite journal}}: CS1 maint: multiple names: authors list (link)
    • Boothby LA, Doering PL (2005). "Vitamin C and vitamin E for Alzheimer's disease". Ann Pharmacother. 39 (12): 2073–80. doi:10.1345/aph.1E495. PMID 16227450.
    • Gray SL, Anderson ML, Crane PK, Breitner JC, McCormick W, Bowen JD, Teri L, Larson E (2008). "Antioxidant vitamin supplement use and risk of dementia or Alzheimer's disease in older adults". J Am Geriatr Soc. 56 (2): 291–295. doi:10.1111/j.1532-5415.2007.01531.x. PMID 18047492.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  107. ^ Curcumin in diet:
    • Garcia-Alloza M, Borrelli LA, Rozkalne A, Hyman BT, Bacskai BJ (2007). "Curcumin labels amyloid pathology in vivo, disrupts existing plaques, and partially restores distorted neurites in an Alzheimer mouse model". Journal of Neurochemistry. 102 (4): 1095–1104. doi:10.1111/j.1471-4159.2007.04613.x. PMID 17472706.{{cite journal}}: CS1 maint: multiple names: authors list (link)
    • Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM (2001). "The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse". Journal of Neuroscience. 21 (21): 8370–8377. PMID 11606625.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  108. ^ Rosendorff C, Beeri MS, Silverman JM (2007). "Cardiovascular risk factors for Alzheimer's disease". Am J Geriatr Cardiol. 16 (3): 143–9. doi:10.1111/j.1076-7460.2007.06696.x. PMID 17483665.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  109. ^ Patterson C, Feightner JW, Garcia A, Hsiung GY, MacKnight C, Sadovnick AD (2008). "Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease". CMAJ. 178 (5): 548–56. doi:10.1503/cmaj.070796. PMC 2244657. PMID 18299540. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  110. ^ Reiss AB, Wirkowski E (2007). "Role of HMG-CoA reductase inhibitors in neurological disorders : progress to date". Drugs. 67 (15): 2111–20. doi:10.2165/00003495-200767150-00001. PMID 17927279.
  111. ^ Kuller LH (2007). "Statins and dementia". Curr Atheroscler Rep. 9 (2): 154–61. doi:10.1007/s11883-007-0012-9. PMID 17877925. {{cite journal}}: Unknown parameter |month= ignored (help)
  112. ^ Szekely CA, Breitner JC, Fitzpatrick AL; et al. (2008). "NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type". Neurology. 70 (1): 17–24. doi:10.1212/01.wnl.0000284596.95156.48. PMID 18003940. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  113. ^ Vlad SC, Miller DR, Kowall NW, Felson DT (2008). "Protective effects of NSAIDs on the development of Alzheimer disease". Neurology. 70 (19): 1672–7. doi:10.1212/01.wnl.0000311269.57716.63. PMID 18458226. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  114. ^ Craig MC, Murphy DG (2007). "Estrogen: effects on normal brain function and neuropsychiatric disorders". Climacteric. 10 Suppl 2: 97–104. doi:10.1080/13697130701598746. PMID 17882683. {{cite journal}}: Unknown parameter |month= ignored (help)
  115. ^ Mori K, Takeda M (2007). "[Hormone replacement Up-to-date. Hormone replacement therapy and brain function]". Clin Calcium (in Japanese). 17 (9): 1349–54. doi:CliCa070913491354. PMID 17767023. {{cite journal}}: Check |doi= value (help); Unknown parameter |doi_brokendate= ignored (|doi-broken-date= suggested) (help); Unknown parameter |month= ignored (help)
  116. ^ Birks J, Grimley Evans J (2007). "Ginkgo biloba for cognitive impairment and dementia". Cochrane Database Syst Rev (2): CD003120. doi:10.1002/14651858.CD003120.pub2. PMID 17443523. Retrieved 2008-02-22.
  117. ^ DeKosky ST, Williamson JD, Fitzpatrick AL; et al. (2008). "Ginkgo biloba for Prevention of Dementia". Journal of the American Medical Association. 300 (19): 2253–2262. doi:10.1001/jama.2008.683. PMID 19017911. Retrieved 2008-11-18. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  118. ^ Verghese J, Lipton RB, Katz MJ; et al. (2003). "Leisure activities and the risk of dementia in the elderly". N. Engl. J. Med. 348 (25): 2508–16. doi:10.1056/NEJMoa022252. PMID 12815136. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  119. ^ Bennett DA, Schneider JA, Tang Y, Arnold SE, Wilson RS (2006). "The effect of social networks on the relation between Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort study". Lancet Neurol. 5 (5): 406–412. doi:10.1016/S1474-4422(06)70417-3. PMID 16632311.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  120. ^ Bialystok E, Craik FIM, Freedman M (2007). "Bilingualism as a protection against the onset of symptoms of dementia". Neuropsychologia. 42 (2): 459–464. doi:10.1016/j.neuropsychologia.2006.10.009.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  121. ^ Davanipour Z, Tseng CC, Lee PJ, Sobel E (2007). "A case-control study of occupational magnetic field exposure and Alzheimer's disease: results from the California Alzheimer's Disease Diagnosis and Treatment Centers". BMC Neurol. 7: 13. doi:10.1186/1471-2377-7-13. PMC 1906833. PMID 17559686.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  122. ^ Qiu C, Fratiglioni L, Karp A, Winblad B, Bellander T (2004). "Occupational exposure to electromagnetic fields and risk of Alzheimer's disease". Epidemiology. 15 (6): 687–94. doi:10.1097/01.ede.0000142147.49297.9d. PMID 15475717. Retrieved 2008-09-22. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  123. ^ Shcherbatykh I, Carpenter DO (2007). "The role of metals in the etiology of Alzheimer's disease". J. Alzheimers Dis. 11 (2): 191–205. PMID 17522444. {{cite journal}}: Unknown parameter |month= ignored (help)
  124. ^ Rondeau V, Commenges D, Jacqmin-Gadda H, Dartigues JF (2000). "Relation between aluminum concentrations in drinking water and Alzheimer's disease: an 8-year follow-up study". Am. J. Epidemiol. 152 (1): 59–66. doi:10.1093/aje/152.1.59. PMC 2215380. PMID 10901330. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  125. ^ Kukull WA, Larson EB, Bowen JD; et al. (1995). "Solvent exposure as a risk factor for Alzheimer's disease: a case-control study". Am. J. Epidemiol. 141 (11): 1059–71, discussion 1072–9. PMID 7771442. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  126. ^ Santibáñez M, Bolumar F, García AM (2007). "Occupational risk factors in Alzheimer's disease: a review assessing the quality of published epidemiological studies". Occupational and Environmental Medicine. 64 (11): 723–732. doi:10.1136/oem.2006.028209. PMID 17525096.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  127. ^ Seidler A, Geller P, Nienhaus A; et al. (2007). "Occupational exposure to low frequency magnetic fields and dementia: a case-control study". Occup Environ Med. 64 (2): 108–14. doi:10.1136/oem.2005.024190. PMID 17043077. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  128. ^ Rondeau V (2002). "A review of epidemiologic studies on aluminum and silica in relation to Alzheimer's disease and associated disorders". Rev Environ Health. 17 (2): 107–21. PMID 12222737.
  129. ^ Martyn CN, Coggon DN, Inskip H, Lacey RF, Young WF (1997). "Aluminum concentrations in drinking water and risk of Alzheimer's disease". Epidemiology. 8 (3): 281–6. doi:10.1097/00001648-199705000-00009. PMID 9115023. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  130. ^ Graves AB, Rosner D, Echeverria D, Mortimer JA, Larson EB (1998). "Occupational exposures to solvents and aluminium and estimated risk of Alzheimer's disease". Occup Environ Med. 55 (9): 627–33. doi:10.1136/oem.55.9.627. PMC 1757634. PMID 9861186. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  131. ^ Geula C, Mesulam MM (1995). "Cholinesterases and the pathology of Alzheimer disease". Alzheimer Dis Assoc Disord. 9 Suppl 2: 23–28. PMID 8534419.
  132. ^ Stahl SM (2000). "The new cholinesterase inhibitors for Alzheimer's disease, Part 2: illustrating their mechanisms of action". J Clin Psychiatry. 61 (11): 813–814. PMID 11105732.
  133. ^ "Donepezil". US National Library of Medicine (Medline Plus). 2007-01-08. Retrieved 2008-03-20.
  134. ^ "Galantamine". US National Library of Medicine (Medline Plus). 2007-01-08. Retrieved 2008-03-20.
  135. ^ "Rivastigmine". US National Library of Medicine (Medline Plus). 2007-01-08. Retrieved 2008-03-20.
  136. ^ "Rivastigmine Transdermal". US National Library of Medicine (Medline Plus). 2007-01-08. Retrieved 2008-03-20.
  137. ^ Birks J (2006). "Cholinesterase inhibitors for Alzheimer's disease". Cochrane Database Syst Rev (1): CD005593. doi:10.1002/14651858.CD005593. PMID 16437532.
  138. ^ Birks J, Harvey RJ (2006). "Donepezil for dementia due to Alzheimer's disease". Cochrane Database Syst Rev (1): CD001190. doi:10.1002/14651858.CD001190.pub2. PMID 16437430.
  139. ^ Raschetti R, Albanese E, Vanacore N, Maggini M (2007). "Cholinesterase inhibitors in mild cognitive impairment: a systematic review of randomised trials". PLoS Med. 4 (11): e338. doi:10.1371/journal.pmed.0040338. PMID 18044984.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  140. ^ Acetylcholinesterase inhibitors prescribing information:
  141. ^ a b Lipton SA (2006). "Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond". Nat Rev Drug Discov. 5 (2): 160–170. doi:10.1038/nrd1958. PMID 16424917.
  142. ^ "Memantine". US National Library of Medicine (Medline). 2004-01-04. Retrieved 2008-03-22.
  143. ^ Areosa Sastre A, McShane R, Sherriff F (2004). "Memantine for dementia". Cochrane Database Syst Rev (4): CD003154. doi:10.1002/14651858.CD003154.pub2. PMID 15495043.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  144. ^ "Namenda Prescribing Information" (PDF). Forest Pharmaceuticals. Retrieved 2008-02-19.
  145. ^ Raina P, Santaguida P, Ismaila A; et al. (2008). "Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline". Annals of Internal Medicine. 148 (5): 379–397. PMID 18316756. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  146. ^ Antipsychotics use:
    • Ballard C, Waite J (2006). "The effectiveness of atypical antipsychotics for the treatment of aggression and psychosis in Alzheimer's disease". Cochrane Database Syst Rev (1): CD003476. doi:10.1002/14651858.CD003476.pub2. PMID 16437455.
    • Ballard C, Lana MM, Theodoulou M; et al. (2008). "A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial)". PLoS Med. 5 (4): e76. doi:10.1371/journal.pmed.0050076. PMID 18384230. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
    • Sink KM, Holden KF, Yaffe K (2005). "Pharmacological treatment of neuropsychiatric symptoms of dementia: a review of the evidence". JAMA. 293 (5): 596–608. doi:10.1001/jama.293.5.596. PMID 15687315.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  147. ^ a b Ballard C, Hanney ML, Theodoulou M, Douglas S, McShane R, Kossakowski K, Gill R, Juszczak E, Yu L-M, Jacoby R (9 January 2009). "The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial". Lancet Neurology. 8: 151. doi:10.1016/S1474-4422(08)70295-3. PMID 19138567. {{cite journal}}: Unknown parameter |laysummary= ignored (help)CS1 maint: multiple names: authors list (link)
  148. ^ a b c d e f g "Practice Guideline for the Treatment of Patients with Alzheimer's disease and Other Dementias" (PDF). American Psychiatric Association. 2007. doi:10.1176/appi.books.9780890423967.152139. Retrieved 2007-12-28. {{cite web}}: Unknown parameter |month= ignored (help)
  149. ^ Bottino CM, Carvalho IA, Alvarez AM; et al. (2005). "Cognitive rehabilitation combined with drug treatment in Alzheimer's disease patients: a pilot study". Clin Rehabil. 19 (8): 861–869. doi:10.1191/0269215505cr911oa. PMID 16323385. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  150. ^ Doody RS, Stevens JC, Beck C; et al. (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): 1154–1166. PMID 11342679. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  151. ^ Hermans DG, Htay UH, McShane R (2007). "Non-pharmacological interventions for wandering of people with dementia in the domestic setting". Cochrane Database Syst Rev (1): CD005994. doi:10.1002/14651858.CD005994.pub2. PMID 17253573.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  152. ^ Robinson L, Hutchings D, Dickinson HO; et al. (2007). "Effectiveness and acceptability of non-pharmacological interventions to reduce wandering in dementia: a systematic review". Int J Geriatr Psychiatry. 22 (1): 9–22. doi:10.1002/gps.1643. PMID 17096455. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  153. ^ Woods B, Spector A, Jones C, Orrell M, Davies S (2005). "Reminiscence therapy for dementia". Cochrane Database Syst Rev (2): CD001120. doi:10.1002/14651858.CD001120.pub2. PMID 15846613.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  154. ^ Peak JS, Cheston RI (2002). "Using simulated presence therapy with people with dementia". Aging Ment Health. 6 (1): 77–81. doi:10.1080/13607860120101095. PMID 11827626.
  155. ^ Camberg L, Woods P, Ooi WL; et al. (1999). "Evaluation of Simulated Presence: a personalised approach to enhance well-being in persons with Alzheimer's disease". J Am Geriatr Soc. 47 (4): 446–452. PMID 10203120. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  156. ^ Neal M, Briggs M (2003). "Validation therapy for dementia". Cochrane Database Syst Rev (3): CD001394. doi:10.1002/14651858.CD001394. PMID 12917907.
  157. ^ Chung JC, Lai CK, Chung PM, French HP (2002). "Snoezelen for dementia". Cochrane Database Syst Rev (4): CD003152. doi:10.1002/14651858.CD003152. PMID 12519587.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  158. ^ Spector A, Orrell M, Davies S, Woods B (2000). "Withdrawn: Reality orientation for dementia". Cochrane Database Syst Rev (3): CD001119. doi:10.1002/14651858.CD001119.pub2. PMID 17636652.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  159. ^ Spector A, Thorgrimsen L, Woods B; et al. (2003). "Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia: randomised controlled trial". Br J Psychiatry. 183: 248–254. doi:10.1192/bjp.183.3.248. PMID 12948999. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  160. ^ Gitlin LN, Corcoran M, Winter L, Boyce A, Hauck WW (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". Gerontologist. 41 (1): 4–14. PMID 11220813. Retrieved 2008-07-15. {{cite journal}}: Unknown parameter |day= ignored (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  161. ^ Gitlin LN, Hauck WW, Dennis MP, Winter L (2005). "Maintenance of effects of the home environmental skill-building program for family caregivers and individuals with Alzheimer's disease and related disorders". J. Gerontol. A Biol. Sci. Med. Sci. 60 (3): 368–74. PMID 15860476. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  162. ^ "Treating behavioral and psychiatric symptoms". Alzheimer's Association. 2006. Retrieved 2006-09-25.
  163. ^ Dunne TE, Neargarder SA, Cipolloni PB, Cronin-Golomb A (2004). "Visual contrast enhances food and liquid intake in advanced Alzheimer's disease". Clinical Nutrition. 23 (4): 533–538. doi:10.1016/j.clnu.2003.09.015. PMID 15297089.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  164. ^ Dudek, Susan G. (2007). Nutrition essentials for nursing practice. Hagerstown, Maryland: Lippincott Williams & Wilkins. p. 360. ISBN 0-7817-6651-6. Retrieved 2008-08-19.
  165. ^ Dennehy C (2006). "Analysis of patients' rights: dementia and PEG insertion". Br J Nurs. 15 (1): 18–20. PMID 16415742.
  166. ^ Chernoff R (2006). "Tube feeding patients with dementia". Nutr Clin Pract. 21 (2): 142–6. doi:10.1177/0115426506021002142. PMID 16556924. {{cite journal}}: Unknown parameter |month= ignored (help)
  167. ^ Medical issues:
    • Head B (2003). "Palliative care for persons with dementia". Home Healthc Nurse. 21 (1): 53–60, quiz 61. doi:10.1097/00004045-200301000-00012. PMID 12544465. {{cite journal}}: Unknown parameter |month= ignored (help)
    • Friedlander AH, Norman DC, Mahler ME, Norman KM, Yagiela JA (2006). "Alzheimer's disease: psychopathology, medical management and dental implications". J Am Dent Assoc. 137 (9): 1240–51. PMID 16946428. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
    • 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". J Nutr Health Aging. 11 (1): 33–7. PMID 17315078.
    • McCurry SM, Gibbons LE, Logsdon RG, Vitiello M, Teri L (2003). "Training caregivers to change the sleep hygiene practices of patients with dementia: the NITE-AD project". J Am Geriatr Soc. 51 (10): 1455–60. doi:10.1046/j.1532-5415.2003.51466.x. PMID 14511168. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
    • Perls TT, Herget M (1995). "Higher respiratory infection rates on an Alzheimer's special care unit and successful intervention". J Am Geriatr Soc. 43 (12): 1341–4. PMID 7490383. {{cite journal}}: Unknown parameter |month= ignored (help)
  168. ^ Shega JW, Levin A, Hougham GW; et al. (2003). "Palliative Excellence in Alzheimer Care Efforts (PEACE): a program description". J Palliat Med. 6 (2): 315–20. doi:10.1089/109662103764978641. PMID 12854952. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  169. ^ a b Bowen JD, Malter AD, Sheppard L; et al. (1996). "Predictors of mortality in patients diagnosed with probable Alzheimer's disease". Neurology. 47 (2): 433–9. PMID 8757016. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  170. ^ a b Dodge HH, Shen C, Pandav R, DeKosky ST, Ganguli M (2003). "Functional transitions and active life expectancy associated with Alzheimer disease". Arch. Neurol. 60 (2): 253–9. doi:10.1001/archneur.60.2.253. PMID 12580712. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  171. ^ Larson EB, Shadlen MF, Wang L; et al. (2004). "Survival after initial diagnosis of Alzheimer disease". Ann. Intern. Med. 140 (7): 501–9. PMID 15068977. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  172. ^ Jagger C, Clarke M, Stone A (1995). "Predictors of survival with Alzheimer's disease: a community-based study". Psychol Med. 25 (1): 171–7. PMID 7792352. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  173. ^ a b Ganguli M, Dodge HH, Shen C, Pandav RS, DeKosky ST (2005). "Alzheimer disease and mortality: a 15-year epidemiological study". Arch. Neurol. 62 (5): 779–84. doi:10.1001/archneur.62.5.779. PMID 15883266. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  174. ^ a b c Bermejo-Pareja F, Benito-León J, Vega S, Medrano MJ, Román GC (2008). "Incidence and subtypes of dementia in three elderly populations of central Spain". J. Neurol. Sci. 264 (1–2): 63–72. doi:10.1016/j.jns.2007.07.021. PMID 17727890. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  175. ^ a b c Di Carlo A, Baldereschi M, Amaducci L; et al. (2002). "Incidence of dementia, Alzheimer's disease, and vascular dementia in Italy. The ILSA Study". J Am Geriatr Soc. 50 (1): 41–8. doi:10.1046/j.1532-5415.2002.50006.x. PMID 12028245. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  176. ^ Andersen K, Launer LJ, Dewey ME; et al. (1999). "Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group". Neurology. 53 (9): 1992–7. PMID 10599770. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  177. ^ 2000 U.S. estimates:
  178. ^ a b Ferri CP, Prince M, Brayne C; et al. (2005). "Global prevalence of dementia: a Delphi consensus study" (PDF). Lancet. 366 (9503): 2112–7. doi:10.1016/S0140-6736(05)67889-0. PMID 16360788. Retrieved 2008-06-13. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  179. ^ World Health Organization (2006). Neurological Disorders: Public Health Challenges. Switzerland: World Health Organization. pp. 204–207. ISBN 978-92-4-156336-9.
  180. ^ Auguste D.:
    • Alzheimer Alois (1907). "Über eine eigenartige Erkrankung der Hirnrinde [About a peculiar disease of the cerebral cortex]". Allgemeine Zeitschrift fur Psychiatrie und Psychisch-Gerichtlich Medizin (in Template:De icon). 64 (1–2): 146–148.{{cite journal}}: CS1 maint: unrecognized language (link)
    • Alzheimer Alois (1987). "About a peculiar disease of the cerebral cortex. By Alois Alzheimer, 1907 (Translated by L. Jarvik and H. Greenson)". Alzheimer Dis Assoc Disord. 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. ISBN 0-231-11896-1.
  181. ^ Kraepelin Emil, Diefendorf A. Ross (translated by) (2007-01-17). Clinical Psychiatry: A Textbook For Students And Physicians (Reprint). Kessinger Publishing. p. 568. ISBN 1-4325-0833-4.
  182. ^ Katzman Robert, Terry Robert D, Bick Katherine L (editors) (1978). Alzheimer's disease: senile dementia and related disorders. New York: Raven Press. p. 595. ISBN 0-89004-225-X. {{cite book}}: |author= has generic name (help)CS1 maint: multiple names: authors list (link)
  183. ^ Boller F, Forbes MM (1998). "History of dementia and dementia in history: an overview". J. Neurol. Sci. 158 (2): 125–33. doi:10.1016/S0022-510X(98)00128-2. PMID 9702682. {{cite journal}}: Unknown parameter |month= ignored (help)
  184. ^ Amaducci LA, Rocca WA, Schoenberg BS (1986). "Origin of the distinction between Alzheimer's disease and senile dementia: how history can clarify nosology". Neurology. 36 (11): 1497–9. PMID 3531918. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  185. ^ Allegri RF, Butman J, Arizaga RL; et al. (2007). "Economic impact of dementia in developing countries: an evaluation of costs of Alzheimer-type dementia in Argentina". Int Psychogeriatr. 19 (4): 705–18. doi:10.1017/S1041610206003784. PMID 16870037. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  186. ^ Suh GH, Knapp M, Kang CJ (2006). "The economic costs of dementia in Korea, 2002". Int J Geriatr Psychiatry. 21 (8): 722–8. doi:10.1002/gps.1552. PMID 16858741. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  187. ^ Wimo A, Jonsson L, Winblad B (2006). "An estimate of the worldwide prevalence and direct costs of dementia in 2003". Dement Geriatr Cogn Disord. 21 (3): 175–81. doi:10.1159/000090733. PMID 16401889.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  188. ^ a b c Moore MJ, Zhu CW, Clipp EC (2001). "Informal costs of dementia care: estimates from the National Longitudinal Caregiver Study". J Gerontol B Psychol Sci Soc Sci. 56 (4): S219–28. PMID 11445614. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  189. ^ Jönsson L, Eriksdotter Jönhagen M, Kilander L; et al. (2006). "Determinants of costs of care for patients with Alzheimer's disease". Int J Geriatr Psychiatry. 21 (5): 449–59. doi:10.1002/gps.1489. PMID 16676288. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  190. ^ a b Zhu CW, Sano M (2006). "Economic considerations in the management of Alzheimer's disease". Clin Interv Aging. 1 (2): 143–54. doi:10.2147/ciia.2006.1.2.143. PMID 18044111.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  191. ^ Gaugler JE, Kane RL, Kane RA, Newcomer R (2005). "Early community-based service utilization and its effects on institutionalization in dementia caregiving". Gerontologist. 45 (2): 177–85. PMID 15799982. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  192. ^ Ritchie K, Lovestone S (2002). "The dementias". Lancet. 360 (9347): 1759–66. doi:10.1016/S0140-6736(02)11667-9. PMID 12480441. {{cite journal}}: Unknown parameter |month= ignored (help)
  193. ^ Brodaty H, Hadzi-Pavlovic D (1990). "Psychosocial effects on carers of living with persons with dementia". Aust N Z J Psychiatry. 24 (3): 351–61. doi:10.3109/00048679009077702. PMID 2241719. {{cite journal}}: Unknown parameter |month= ignored (help)
  194. ^ Donaldson C, Tarrier N, Burns A (1998). "Determinants of carer stress in Alzheimer's disease". Int J Geriatr Psychiatry. 13 (4): 248–56. doi:10.1002/(SICI)1099-1166(199804)13:4<248::AID-GPS770>3.0.CO;2-0. PMID 9646153. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  195. ^ "The MetLife Study of Alzheimer's Disease: The Caregiving Experience" (PDF). MetLife Mature Market Institute. 2006. Retrieved 2008-02-12. {{cite web}}: Unknown parameter |month= ignored (help)
  196. ^ Pusey H, Richards D (2001). "A systematic review of the effectiveness of psychosocial interventions for carers of people with dementia". Aging Ment Health. 5 (2): 107–19. doi:10.1080/13607860120038302. PMID 11511058. {{cite journal}}: Unknown parameter |month= ignored (help)
  197. ^ Garrard P, Maloney LM, Hodges JR, Patterson K (2005). "The effects of very early Alzheimer's disease on the characteristics of writing by a renowned author". Brain. 128 (Pt 2): 250–60. doi:10.1093/brain/awh341. PMID 15574466. {{cite journal}}: External link in |title= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  198. ^ Sherman FT (2004). "Did President Reagan have mild cognitive impairment while in office? Living longer with Alzheimer's Disease". Geriatrics. 59 (9): 11, 15. PMID 15461232. {{cite journal}}: External link in |title= (help); Unknown parameter |month= ignored (help)
  199. ^ Venneri A, Forbes-Mckay KE, Shanks MF (2005). "Impoverishment of spontaneous language and the prediction of Alzheimer's disease". Brain. 128 (Pt 4): E27. doi:10.1093/brain/awh419. PMID 15788549. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  200. ^ "Hungary legend Puskas dies at 79". BBC News. 2006-11-17. Retrieved 2008-01-25.
  201. ^ "Prime Ministers in History: Harold Wilson". London: 10 Downing Street. Retrieved 2008-08-18.
  202. ^ ""Mi padre no reconoció al Rey pero notó el cariño"". Madrid: El País. 2008. Retrieved 2008-10-01.
  203. ^ "Chicago Rita Hayworth Gala". Alzheimer’s Association. 2007. Retrieved 2008-01-25.
  204. ^ "Charlton Heston has Alzheimer's symptoms". CNN. 2002-08-09. Retrieved 2008-01-25.
  205. ^ Pauli Michelle (2007-12-12). "Pratchett announces he has Alzheimer's". Guardian News and Media. Retrieved 2008-08-18.
  206. ^ "Iris". IMDB. 2002-01-18. Retrieved 2008-01-24.
  207. ^ Bayley John (2000). Iris: a memoir of Iris Murdoch. London: Abacus. ISBN 9780349112152. OCLC 41960006.
  208. ^ "The notebook". IMDB. Retrieved 2008-02-22.
  209. ^ Sparks Nicholas (1996). The notebook. Thorndike, Maine: Thorndike Press. p. 268. ISBN 078620821X.
  210. ^ "Thanmathra". Webindia123.com. Retrieved 2008-01-24.
  211. ^ "Ashita no kioku". IMDB. Retrieved 2008-01-24. {{cite web}}: Unknown parameter |originallanguage= ignored (help)
  212. ^ Ogiwara Hiroshi (2004). Ashita no Kioku (in Template:Jp icon). Tōkyō: Kōbunsha. ISBN 9784334924461. OCLC 57352130.{{cite book}}: CS1 maint: unrecognized language (link)
  213. ^ Munro Alice (2001). Hateship, Friendship, Courtship, Loveship, Marriage: Stories. New York: A.A. Knopf. ISBN 9780375413001. OCLC 46929223. {{cite book}}: Unknown parameter |chaptertitle= ignored (help)
  214. ^ Malcolm and Barbara:
  215. ^ "Clinical Trials. Found 459 studies with search of: alzheimer". US National Institutes of Health. Retrieved 2008-03-23.
  216. ^ Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJH (2002). "New class of inhibitors of [[Beta amyloid|amyloid-beta]] fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease". J Biol Chem. 277: 42881–42890. PMID 12167652. {{cite journal}}: URL–wikilink conflict (help)CS1 maint: multiple names: authors list (link)
  217. ^ Vaccination:
  218. ^ "Study Evaluating ACC-001 in Mild to Moderate Alzheimers Disease Subjects". Clinical Trial. US National Institutes of Health. 2008-03-11. Retrieved 2008-06-05.
  219. ^ "Study Evaluating Safety, Tolerability, and Immunogenicity of ACC-001 in Subjects With Alzheimer's Disease". US National Institutes of Health. Retrieved 2008-06-05.
  220. ^ "Alzheimer's Disease Vaccine Trial Suspended on Safety Concern". Medpage Today. 2008-04-18. Retrieved 2008-06-14.
  221. ^ "Bapineuzumab in Patients With Mild to Moderate Alzheimer's Disease/ Apo_e4 non-carriers". Clinical Trial. US National Institutes of Health. 2008-02-29. Retrieved 2008-03-23.
  222. ^ "Safety, Tolerability and Efficacy Study to Evaluate Subjects With Mild Cognitive Impairment". Clinical Trial. US National Institutes of Health. 2008-03-11. Retrieved 2008-03-23.
  223. ^ "Study Evaluating the Safety, Tolerability and Efficacy of PBT2 in Patients With Early Alzheimer's Disease". Clinical Trial. US National Institutes of Health. 2008-01-13. Retrieved 2008-03-23.
  224. ^ Etanercept research:
  225. ^ Wischik Claude M, Bentham Peter, Wischik Damon J, Seng Kwang Meng (2008). "Tau aggregation inhibitor (TAI) therapy with remberTM arrests disease progression in mild and moderate Alzheimer's disease over 50 weeks". Alzheimer's & Dementia. 4 (4). Alzheimer’s Association: T167. doi:10.1016/j.jalz.2008.05.438. Retrieved 2008-07-30. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  226. ^ Harrington Charles, Rickard Janet E, Horsley David; et al. (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. Alzheimer’s Association: T120–T121. doi:10.1016/j.jalz.2008.05.259. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  227. ^ Doody RS, Gavrilova SI, Sano M; et al. (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. PMID 18640457. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

Further reading

Listen to this article
(2 parts, 46 minutes)
  2. Part 2
Spoken Wikipedia icon
These audio files were created from a revision of this article dated
Error: no date provided
, and do not reflect subsequent edits.
(Audio help · More spoken articles)

Retrieved from "https://en.wikipedia.org/enwiki/w/index.php?title=Alzheimer%27s_disease&oldid=289964414"