Alzheimer’s Disease

Alzheimer’s disease (AD), also known in medical literature as Alzheimer disease, is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death. It was first described by German psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him. [1] Most often, AD is diagnosed in people over 65 years of age,[2] although the less-prevalent early-onset Alzheimer’s can occur much earlier. In 2006, there were 26. 6 million sufferers worldwide. Alzheimer’s is predicted to affect 1 in 85 people globally by 2050.

[3] Although Alzheimer’s disease develops differently for every individual, there are many common symptoms. [4] Early symptoms are often mistakenly thought to be ‘age-related’ concerns, or manifestations of stress. [5] In the early stages, the most common symptom is difficulty in remembering recent events. When AD is suspected, the diagnosis is usually confirmed with tests that evaluate behaviour and thinking abilities, often followed by a brain scan if available,[6] however, examination of brain tissue is required for a definitive diagnosis.

As the disease advances, symptoms can include confusion, irritability, aggression, mood swings, trouble with language, and long-term memory loss. As the sufferer declines they often withdraw from family and society. [5][7] Gradually, bodily functions are lost, ultimately leading to death. [8] Since the disease is different for each individual, predicting how it will affect the person is difficult. AD develops for an unknown and variable amount of time before becoming fully apparent, and it can progress undiagnosed for years.

On average, the life expectancy following diagnosis is approximately seven years. [9] Fewer than three percent 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] Current treatments only help with the symptoms of the disease. There are no available treatments that stop or reverse the progression of the disease. As of 2012, more than 1,000 clinical trials have been or are being conducted to test various compounds in AD.

[12] Mental stimulation, exercise, and a balanced diet have been suggested as ways to delay cognitive symptoms (though not brain pathology) in healthy older individuals, but there is no conclusive evidence supporting an effect. [13] Because AD cannot be cured and is degenerative, the sufferer relies on others for assistance. 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 costly diseases to society. [18][19] Pre-dementia The first symptoms are often mistakenly attributed to ageing or stress. [5] Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfils the clinical criteria for diagnosis of AD. [21] These early symptoms can affect the most complex daily living activities. [22] The most noticeable deficit is memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information.

[21][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. [21] Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease. [24] Depressive symptoms, irritability and reduced awareness of subtle memory difficulties also occur commonly.

[25] The preclinical stage of the disease has also been termed mild cognitive impairment,[23] but whether this term corresponds to a different diagnostic stage or identifies the first step of AD is a matter of dispute. [26] Early In people with AD the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small portion of them, difficulties with language, executive functions, perception (agnosia), or execution of movements (apraxia) are more prominent than memory problems. [27] 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. [28][29] Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, which lead to a general impoverishment of oral and written language. [27][30] In this stage, the person with Alzheimer’s is usually capable of communicating basic ideas adequately.

[27][30][31] 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. [27] 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. [27] Moderate Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living.

[27] 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. [27][31] Complex motor sequences become less coordinated as time passes and AD progresses, so the risk of falling increases. [27] During this phase, memory problems worsen, and the person may fail to recognise close relatives. [27] Long-term memory, which was previously intact, becomes impaired. [27] Behavioural and neuropsychiatric changes become more prevalent.

Common manifestations are wandering, irritability and labile affect, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. [27] Sundowning can also appear. [32] Approximately 30% of people with AD develop illusionary misidentifications and other delusional symptoms. [27] Subjects also lose insight of their disease process and limitations (anosognosia). [27] Urinary incontinence can develop. [27] 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. [27][33] Advanced.

During the final stage of AD, the person is completely dependent upon caregivers. [27] Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. [27][31] Despite the loss of verbal language abilities, people can often understand and return emotional signals. [27] Although aggressiveness can still be present, extreme apathy and exhaustion are much more common results. [27] People with AD will ultimately not be able to perform even the simplest tasks without assistance. [27] Muscle mass and mobility deteriorate to the point where they are bedridden, and they lose the ability to feed themselves.

[27] AD is a terminal illness, with the cause of death typically being an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself. [27] Genetics Around 0. 1% of the cases are familial forms of autosomal (not sex-linked) dominant inheritance, which usually have an onset before age 65. [35] 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.

[36] Most mutations in the APP and presenilin genes increase the production of a small protein called A? 42, which is the main component of senile plaques. [37] Some of the mutations merely alter the ratio between A? 42 and the other major forms—e. g. , A? 40—without increasing A? 42 levels. [37][38] This suggests that presenilin mutations can cause disease even if they lower the total amount of A? 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 A?. There exist variants of the APP gene which are protective.

[39] Most cases of Alzheimer’s disease do not exhibit autosomal-dominant inheritance and are termed sporadic AD, in which environmental and genetic differences may act as risk factors. The best known genetic risk factor is the inheritance of the ? 4 allele of the apolipoprotein E (APOE). [40][41] Between 40 and 80% of people with AD possess at least one APOE? 4 allele. [41] The APOE? 4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes. [35] Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance.

For example, certain Nigerian populations do not show the relationship between dose of APOE? 4 and incidence or age-of-onset for Alzheimer’s disease seen in other human populations. [42][43] While early attempts to screen up to 400 candidate genes for association with late-onset sporadic AD (LOAD) resulted in a low yield,[35][36] more recent genome-wide association studies (GWAS) turned up 13 genes (and gene clusters): CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, CD33, CD2AP, ATP5H, EXOC4, CTNNA3, RNF219. [44][45][46] Mutations in the TREM2 gene have been associated with a 3 to 5 times higher risk of developing Alzheimer’s disease.

[47][48] 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. Cholinergic hypothesis The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis,[49] 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,[50] leading to generalised neuroinflammation. [51] Amyloid hypothesis In 1991, the amyloid hypothesis postulated that extracellular beta-amyloid (A? ) deposits are the fundamental cause of the disease. [52][53] Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit AD by 40 years of age.

[54][55] Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. Whilst apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain. [56] 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. [57] An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.

[58] Researchers have been led to suspect non-plaque A? oligomers (aggregates of many monomers) as the primary pathogenic form of A?. These toxic oligomers, also referred to as amyloid-derived diffusible ligands (ADDLs), bind to a surface receptor on neurons and change the structure of the synapse, thereby disrupting neuronal communication. [59] One receptor for A? oligomers may be the prion protein, the same protein that has been linked to mad cow disease and the related human condition, Creutzfeldt–Jakob disease, thus potentially linking the underlying mechanism of these neurodegenerative disorders with that of Alzheimer’s disease.

[60] In 2009, this theory was updated, suggesting that a close relative of the beta-amyloid protein, and not necessarily the beta-amyloid itself, may be a major culprit in the disease. The theory holds that an amyloid-related mechanism that prunes neuronal connections in the brain in the fast-growth phase of early life may be triggered by ageing-related processes in later life to cause the neuronal withering of Alzheimer’s disease. [61] N-APP, a fragment of APP from the peptide’s N-terminus, is adjacent to beta-amyloid and is cleaved from APP by one of the same enzymes.

N-APP triggers the self-destruct pathway by binding to a neuronal receptor called death receptor 6 (DR6, also known as TNFRSF21). [61] DR6 is highly expressed in the human brain regions most affected by Alzheimer’s, so it is possible that the N-APP/DR6 pathway might be hijacked in the ageing brain to cause damage. In this model, beta-amyloid plays a complementary role, by depressing synaptic function. Tau hypothesis The tau hypothesis is the idea that tau protein abnormalities initiate the disease cascade.

[53] In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies. [62] When this occurs, the microtubules disintegrate, collapsing the neuron’s transport system. [63] This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells. [64] Other hypotheses Herpes simplex virus type 1 has also been proposed to play a causative role in people carrying the susceptible versions of the apoE gene.

[65] Some have hypothesized that dietary copper may play a causal role. [66] 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. [67][68][69] Oxidative stress and dys-homeostasis of biometal (biology) metabolism may be significant in the formation of the pathology.

[70][71] 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. [72] It has been shown that norepinephrine stimulates mouse microglia to suppress A? -induced production of cytokines and their phagocytosis of A?. [72] This suggests that degeneration of the locus ceruleus might be responsible for increased A? deposition in AD brains. [72].

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