Saturday, March 7, 2015










Alzheimer's disease

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"Alzheimer" redirects here. For other uses, see Alzheimer (disambiguation).
Alzheimer's disease
Alzheimer's disease brain comparison.jpg
Comparison of a normal aged brain (left) and the brain of a person with Alzheimer's (right). Characteristics that separate the two are pointed out.
Classification and external resources
Patient UKAlzheimer's disease
Alzheimer's disease (AD), also known as Alzheimer disease, or just Alzheimer's, accounts for 60% to 70% of cases of dementia.[1][2] It is a chronic neurodegenerativedisease that usually starts slowly and gets worse over time.[1][2] The most common early symptom is difficulty in remembering recent events (short term memory loss).[1] As the disease advances, symptoms can include: problems with languagedisorientation (including easily getting lost), mood swings, loss of motivation, not managing self care, and behavioural issues.[2][1] As a person's condition declines, she or he often withdraws from family and society.[1] Gradually, bodily functions are lost, ultimately leading to death.[3] Although the speed of progression can vary, the average life expectancy following diagnosis is three to nine years.[4][5]
The cause of Alzheimer's disease is poorly understood.[1] About 70% of the risk is believed to be genetic with many genes usually involved.[6] Other risk factors include: a history of head injuriesdepression or hypertension.[1] The disease process is associated with plaques and tangles in the brain.[6] A probable diagnosis is based on the history of the illness and cognitive testing with medical imaging and blood tests to rule out other possible causes.[7] Initial symptoms are often mistaken for normal ageing.[1]Examination of brain tissue is needed for a definite diagnosis.[6] Mental and physical exercise, and avoiding obesity may decrease the risk of AD.[6] There are no medications or supplements with evidence to support their use.[8]
No treatments stop or reverse its progression, though some may temporarily improve symptoms.[2] Affected people increasingly rely on others for assistance, often placing a burden on the caregiver; the pressures can include social, psychological, physical, and economic elements.[9] Exercise programs are beneficial with respect to activities of daily living and potentially improve outcomes.[10] Treatment of behavioral problems or psychosis due to dementia with antipsychotics is common but not usually recommended due to there often being little benefit and an increased risk of early death.[11][12]
In 2010, there were between 21 and 35 million people worldwide with AD.[4][2] It most often begins in people over 65 years of age, although 4% to 5% of cases are early-onset Alzheimer's which begin before this.[13] It affects about 6% of people 65 years and older.[1] In 2010, dementia resulted in about 486,000 deaths.[14] It was first described by, and later named after, German psychiatrist and pathologist Alois Alzheimer in 1906.[15] In developed countries, AD is one of the most financially costly diseases.[16][17]
Stages of Alzheimer's disease
Effects of ageing on memory but not AD
Early stage Alzheimer's
Middle stage Alzheimer's
  • Deeper difficulty remembering recently learned information[18]
  • Deepening confusion in many circumstances[18]
  • Speech impairment[18]
  • Repeatedly initiating the same conversation[18]
Late stage Alzheimer's
The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment.


The first symptoms are often mistakenly attributed to ageing or stress.[19] 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 short term memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.[20][22]
Subtle problems with the executive functions of attentivenessplanning, 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.[20] Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease.[23] Depressive symptoms, irritability and reduced awareness of subtle memory difficulties are also common.[24] The preclinical stage of the disease has also been termed mild cognitive impairment (MCI).[22]This is often found to be a transitional stage between normal ageing and dementia. MCI can present with a variety of symptoms, and when memory loss is the predominant symptom, it is termed "amnestic MCI" and is frequently seen as a prodromal stage of Alzheimer's disease.[25]


In people with AD, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small percentage, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems.[26] 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.[27][28]
Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, leading to a general impoverishment of oral andwritten language.[26][29] In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately.[26][29][30] While performing fine motor tasks such as writing, drawing or dressing, certain movement coordination and planning difficulties (apraxia) may be present, but they are commonly unnoticed.[26] 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.[26]


Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living.[26] 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.[26][30] Complex motor sequences become less coordinated as time passes and AD progresses, so the risk of falling increases.[26] During this phase, memory problems worsen, and the person may fail to recognise close relatives.[26] Long-term memory, which was previously intact, becomes impaired.[26]
Behavioural and neuropsychiatric changes become more prevalent. Common manifestations are wanderingirritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving.[26] Sundowning can also appear.[31] Approximately 30% of people with AD develop illusionary misidentifications and other delusional symptoms.[26] Subjects also lose insight of their disease process and limitations (anosognosia).[26] Urinary incontinence can develop.[26] These symptoms create stress for relatives and carers, which can be reduced by moving the person from home care to other long-term care facilities.[26][32]


During the final stages, the patient is completely dependent upon caregivers.[26] Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech.[26][30] Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common symptoms. People with Alzheimer's disease will ultimately not be able to perform even the simplest tasks independently; muscle mass and mobility deteriorate to the point where they are bedridden and unable to feed themselves. The cause of death is usually an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself.[26]


The cause for most Alzheimer's cases is still mostly unknown except for 1% to 5% of cases where genetic differences have been identified.[33] Several competing hypotheses exist trying to explain the cause of the disease:


The genetic heritability of Alzheimer's disease (and memory components thereof), based on reviews of twin and family studies, range from 49% to 79%.[34][35] Around 0.1% of the cases are familial forms of autosomal(not sex-linkeddominant inheritance, which have an onset before age 65.[36] This form of the disease is known as early onset familial Alzheimer's disease. Most of autosomal dominant familial AD can be attributed to mutations in one of three genes: those encoding amyloid precursor protein (APP) and presenilins 1 and 2.[37] Most mutations in the APP and presenilin genes increase the production of a small protein called Aβ42, which is the main component of senile plaques.[38] Some of the mutations merely alter the ratio between Aβ42 and the other major forms—e.g., Aβ40—without increasing Aβ42 levels.[38][39] This suggests that presenilin mutations can cause disease even if they lower the total amount of Aβ produced and may point to other roles of presenilin or a role for alterations in the function of APP and/or its fragments other than Aβ. There exist variants of the APP gene which are protective.[40]
Most cases of Alzheimer's disease do not exhibit autosomal-dominant inheritance and are termed sporadic AD, in which environmental and genetic differences may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE).[41][42] Between 40 and 80% of people with AD possess at least one APOEε4 allele.[42] The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes.[36] Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance. For example, certain Nigerian populations do not show the relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations.[43][44] Early attempts to screen up to 400 candidate genes for association with late-onset sporadic AD (LOAD) resulted in a low yield,[36][37] More recent genome-wide association studies (GWAS) have found 19 areas in genes that appear to affect the risk.[45] These genes include: CASS4CELF1,FERMT2HLA-DRB5INPP5DMEF2CNME8PTK2BSORL1ZCWPW1SlC24A4CLUPICALMCR1BIN1MS4AABCA7EPHA1, and CD2AP.[45]
Mutations in the TREM2 gene have been associated with a 3 to 5 times higher risk of developing Alzheimer's disease.[46][47] A suggested mechanism of action is that when TREM2 is mutated, white blood cells in the brain are no longer able to control the amount of beta amyloid present.

Tau hypothesis

In Alzheimer's disease, changes in tau protein lead to the disintegration of microtubules in brain cells.
The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade.[52] 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, destroying the structure of the cell'scytoskeleton which collapses 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]

Other hypotheses

Herpes simplex virus type 1 has been proposed to play a causative role in people carrying the susceptible versions of the apoE gene.[64]
The cellular homeostasis of ionic copper, iron, and zinc is disrupted in AD, though it remains unclear whether this is produced by or causes the changes in proteins. These ions affect and are affected by tau, APP, and APOE.[65] Some studies have shown an increased risk of developing AD with environmental factors such as the intake of metals, particularly aluminium.[66] The quality of some of these studies has been criticised,[67] and other studies have concluded that there is no relationship between these environmental factors and the development of AD.[68] Some have hypothesised that dietary copper may play a causal role.[69]
While some studies suggest that extremely low frequency electromagnetic fields may increase the risk for Alzheimer's disease,[70] reviewers found that further epidemiological and laboratory investigations of this hypothesis are needed.[71] Smoking is a significant AD risk factor.[72] Systemic markers of the innate immune system are risk factors for late-onset AD.[73]
Another hypothesis asserts that the disease may be caused by age-related myelin breakdown in the brain. Iron released during myelin breakdown is hypothesised to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous deposits such as beta-amyloid and tau.[74][75][76]
Oxidative stress and dys-homeostasis of biometal metabolism may be significant in the formation of the pathology.[77][78][79] In this point of view, low molecular weight antioxidants such as melatonin would be promising.[80]
AD individuals show 70% loss of locus coeruleus cells that provide norepinephrine (in addition to its neurotransmitter role) that locally diffuses from "varicosities" as an endogenous anti-inflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus.[81] It has been shown that norepinephrine stimulates mouse microglia to suppress Aβ-induced production of cytokines and their phagocytosis of Aβ.[81] This suggests that degeneration of the locus ceruleus might be responsible for increased Aβ deposition in AD brains.[81]
There is tentative evidence that exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.[82]


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


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.[50] Degeneration is also present in brainstem nuclei like the locus coeruleus.[83] Studies using MRI and PET have documented reductions in the size of specific brain regions in people with AD as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults.[84][85]
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD.[86] Plaques are dense, mostly insoluble deposits of beta-amyloid peptide and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyperphosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of ageing, the brains of people with AD have a greater number of them in specific brain regions such as the temporal lobe.[87] Lewy bodies are not rare in the brains of people with AD.[88]


Enzymes act on the APP (amyloid precursor protein) and cut it into fragments. The beta-amyloid fragment is crucial in the formation of senile plaques in AD.
Alzheimer's disease has been identified as a protein misfolding disease (proteopathy), caused by plaque accumulation of abnormally folded amyloid beta protein, and tau protein in the brain.[89] Plaques are made up of small peptides, 39–43 amino acids in length, called amyloid beta (Aβ). Aβ is a fragment from the larger amyloid precursor protein (APP). APP is a transmembrane protein that penetrates through the neuron's membrane. APP is critical to neuron growth, survival and post-injury repair.[90][91] In Alzheimer's disease, an unknown enzyme in a proteolytic process causes APP to be divided into smaller fragments.[92] One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as senile plaques.[86][93]
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 taustabilises 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.[94]


PET scan of the brain of a person with AD showing a loss of function in the temporal lobe
Alzheimer's disease is usually diagnosed based on the person's medical history, history from relatives, and behavioural observations. The presence of characteristic neurologicaland neuropsychological features and the absence of alternative conditions is supportive.[102][103] 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.[104] Moreover, it may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease.[105]
Assessment of intellectual functioning including memory testing can further characterise the state of the disease.[19] Medical organisations have created diagnostic criteria to ease and standardise the diagnostic process for practising physicians. The diagnosis can be confirmed with very high accuracy post-mortem when brain material is available and can be examined histologically.[106]

Early diagnosis

Emphasis in Alzheimer's research has been placed on diagnosing the condition before symptoms begin.[119] A number of biochemical tests have been developed to allow for early detection. One such test involves the analysis of cerebrospinal fluid for beta-amyloid or tau proteins,[120] both total tau protein and phosphorylated tau181P protein concentrations.[121][122] Searching for these proteins using a spinal tap can predict the onset of Alzheimer's with a sensitivity of between 94% and 100%.[121] When used in conjunction with existing neuroimaging techniques, doctors can identify people with significant memory loss who are already developing the disease.[121]


Intellectual activities such as playingchess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.
At present, there is no definitive evidence to support that any particular measure is effective in preventing AD.[123] Global studies of measures to prevent or delay the onset of AD have often produced inconsistent results. Epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether these factors can help to prevent AD.[124]


Although cardiovascular risk factors, such as hypercholesterolaemiahypertensiondiabetes, and smoking, are associated with a higher risk of onset and course of AD,[125][126]statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease.[127][128]
Long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced likelihood of developing AD.[129] Evidence also support the notion that NSAIDs can reduce inflammation related to amyloid plaques.[129] No prevention trial has been completed.[129] They do not appear to be useful as a treatment.[130] Hormone replacement therapy, although previously used, may increase the risk of dementia.[131]


People who engage in intellectual activities such as reading, playing board games, completing crossword puzzles, playing musical instruments, or regular social interaction show a reduced risk for Alzheimer's disease.[132] This is compatible with the cognitive reserve theory, which states that some life experiences result in more efficient neural functioning providing the individual a cognitive reserve that delays the onset of dementia manifestations.[132] Education delays the onset of AD syndrome, but is not related to earlier death after diagnosis.[133] Learning a second language even later in life seems to delay getting Alzheimer disease.[134] Physical activity is also associated with a reduced risk of AD.[133]


People who eat a healthyJapanese or mediterranean diet have a lower risk of AD,[135] and a mediterranean diet may improve outcomes in those with the disease.[136] Those who eat a diet high in saturated fats and simple carbohydrates have a higher risk.[137] The mediterranean diet's beneficial cardiovascular effect has been proposed as the mechanism of action.[138]
Conclusions on dietary components have at times been difficult to ascertain as results have differed between population-based studies and randomised controlled trials.[135] There is limited evidence that light to moderate use of alcohol, particularly red wine, is associated with lower risk of AD.[139] There is tentative evidence that caffeine may be protective.[140] A number of foods high in flavonoids such as cocoa, red wine, and tea may decrease the risk of AD.[141][142]


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...........


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