alzheimer's disease alzheimer's disease alzheimer's disease (ad) is a neurodegenerative disease that usually starts slowly and progressively worsens. it is the cause of 60–70% of cases of dementia. the most common early symptom is difficulty in remembering recent events. as the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, self-neglect, and behavioral issues. as a person's condition declines, they often withdraw from family and society. gradually, bodily functions are lost, ultimately leading to death. although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years. alzheimer's diseasediagram of a normal brain compared to the brain of a person with alzheimer'spronunciation/ˈæltshaɪmərz/, us also /ˈɑːlts-/ specialtyneurologysymptomsmemory loss, problems with language, disorientation, mood swingscomplicationsdehydration and pneumonia in the terminal stageusual onsetover 65 years olddurationlong termcausespoorly understoodrisk factorsgenetics, head injuries, depression, hypertensiondiagnostic methodbased on symptoms and cognitive testing after ruling out other possible causesdifferential diagnosisnormal brain aging, lewy body dementia, trisomy 21.medicationacetylcholinesterase inhibitors, nmda receptor antagonists (small benefit)prognosislife expectancy 3–9 yearsfrequency50 million (2020) the cause of alzheimer's disease is poorly understood. there are many environmental and genetic risk factors associated with its development. the strongest genetic risk factor is from an allele of apoe. other risk factors include a history of head injury, clinical depression, and high blood pressure. the disease process is largely associated with amyloid plaques, neurofibrillary tangles, and loss of neuronal connections in the brain. 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. initial symptoms are often mistaken for normal brain aging. examination of brain tissue is needed for a definite diagnosis, but this can only take place after death. good nutrition, physical activity, and engaging socially are known to be of benefit generally in aging, and these may help in reducing the risk of cognitive decline and alzheimer's; in 2019 clinical trials were underway to look at these possibilities. there are no medications or supplements that have been shown to decrease risk. no treatments stop or reverse its progression, though some may temporarily improve symptoms. affected people increasingly rely on others for assistance, often placing a burden on the caregiver. the pressures can include social, psychological, physical, and economic elements. exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes. behavioral problems or psychosis due to dementia are often treated with antipsychotics, but this is not usually recommended, as there is little benefit and an increased risk of early death. as of 2020, there were approximately 50 million people worldwide with alzheimer's disease. it most often begins in people over 65 years of age, although up to 10% of cases are early-onset affecting those in their 30s to mid-60s. it affects about 6% of people 65 years and older, and women more often than men. the disease is named after german psychiatrist and pathologist alois alzheimer, who first described it in 1906. alzheimer's financial burden on society is large, with an estimated global annual cost of us$1 trillion. alzheimer's disease is currently ranked as the seventh leading cause of death in the united states. signs and symptoms the course of alzheimer's is generally described in three stages, with a progressive pattern of cognitive and functional impairment. the three stages are described as early or mild, middle or moderate, and late or severe. the disease is known to target the hippocampus which is associated with memory, and this is responsible for the first symptoms of memory impairment. as the disease progresses so does the degree of memory impairment. first symptoms stages of atrophy in alzheimer's the first symptoms are often mistakenly attributed to aging or stress. detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria for diagnosis of alzheimer's disease. these early symptoms can affect the most complex activities of daily living. 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. 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 alzheimer's disease. apathy and depression can be seen at this stage, with apathy remaining as the most persistent symptom throughout the course of the disease. mild cognitive impairment (mci) is often found to be a transitional stage between normal aging 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. amnestic mci has a greater than 90% likelihood of being associated with alzheimer's. early stage in people with alzheimer's disease, 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. alzheimer's disease does not affect all memory capacities equally. older memories of the person's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat or how to drink from a glass) are affected to a lesser degree than new facts or memories. language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, leading to a general impoverishment of oral and written language. in this stage, the person with alzheimer's is usually capable of communicating basic ideas adequately. while performing fine motor tasks such as writing, drawing, or dressing, certain movement coordination and planning difficulties (apraxia) may be present, but they are commonly unnoticed. as the disease progresses, people with alzheimer's disease can often continue to perform many tasks independently, but may need assistance or supervision with the most cognitively demanding activities. middle stage progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living. speech difficulties become evident due to an inability to recall vocabulary, which leads to frequent incorrect word substitutions (paraphasias). reading and writing skills are also progressively lost. complex motor sequences become less coordinated as time passes and alzheimer's disease progresses, so the risk of falling increases. during this phase, memory problems worsen, and the person may fail to recognise close relatives. long-term memory, which was previously intact, becomes impaired. behavioral and neuropsychiatric changes become more prevalent. common manifestations are wandering, irritability and emotional lability, leading to crying, outbursts of unpremeditated aggression, or resistance to caregiving. sundowning can also appear. approximately 30% of people with alzheimer's disease develop illusionary misidentifications and other delusional symptoms. subjects also lose insight of their disease process and limitations (anosognosia). urinary incontinence can develop. these symptoms create stress for relatives and caregivers, which can be reduced by moving the person from home care to other long-term care facilities. late stage a normal brain on the left and a late-stage alzheimer's brain on the right during the final stage, known as the late-stage or severe stage, there is complete dependence on caregivers. language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. despite the loss of verbal language abilities, people can often understand and return emotional signals. although aggressiveness can still be present, extreme apathy and exhaustion are much more common symptoms. people with alzheimer's disease will ultimately not be able to perform even the simplest tasks independently; muscle mass and mobility deteriorates to the point where they are bedridden and unable to feed themselves. the cause of death is usually an external factor, such as infection of pressure ulcers or pneumonia, not the disease itself. in some cases, there is a paradoxical lucidity immediately before death, where there is an unexpected recovery of mental clarity. familial and nonfamilial alzheimer's disease familial alzheimer's disease is an inherited and uncommon form of alzheimer's disease. familial ad usually strikes earlier in life, defined as before the age of 65. fad usually implies multiple persons affected in one or more generation. sporadic alzheimer's disease (or nonfamilial alzheimer's disease) describes all other cases, where genetic risk factors are minor or unclear. causes proteins fail to function normally. this disrupts the work of the brain cells affected and triggers a toxic cascade, ultimately leading to cell death and later brain shrinkage. alzheimer's disease is believed to occur when abnormal amounts of amyloid beta (aβ), accumulating extracellularly as amyloid plaques and tau proteins, or intracellularly as neurofibrillary tangles, form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function. this altered protein clearance ability is age-related, regulated by brain cholesterol, and associated with other neurodegenerative diseases. advances in brain imaging techniques allow researchers to see the development and spread of abnormal amyloid and tau proteins in the living brain, as well as changes in brain structure and function. beta-amyloid is a fragment of a larger protein. when these fragments cluster together, a toxic effect appears on neurons and disrupt cell-to-cell communication. larger deposits called amyloid plaques are thus further formed. tau proteins are responsible in neuron's internal support and transport system to carry nutrients and other essential materials. in alzheimer's disease, the shape of tau proteins is altered and thus organize themselves into structures called neurofibrillary tangles. the tangles disrupt the transport system and are toxic to cells. the cause for most alzheimer's cases is still mostly unknown, except for 1–2% of cases where deterministic genetic differences have been identified. several competing hypotheses attempt to explain the underlying cause; the two predominant hypotheses are the amyloid beta (aβ) hypothesis and the cholinergic hypothesis. the oldest hypothesis, on which most drug therapies are based, is the cholinergic hypothesis, which proposes that alzheimer's disease is caused by reduced synthesis of the neurotransmitter acetylcholine. the loss of cholinergic neurons noted in the limbic system and cerebral cortex, is a key feature in the progression of alzheimer's. the 1991 amyloid hypothesis postulated that extracellular amyloid beta (aβ) deposits are the fundamental cause of the disease. support for this postulate comes from the location of the gene for the amyloid precursor protein (app) on chromosome 21, together with the fact that people with trisomy 21 (down syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of alzheimer's disease by 40 years of age. a specific isoform of apolipoprotein, apoe4, is a major genetic risk factor for alzheimer's disease. while apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as apoe4), leading to excess amyloid buildup in the brain. genetic only 1–2% of alzheimer's cases are inherited (autosomal dominant). these types are known as early onset familial alzheimer's disease, can have a very early onset, and a faster rate of progression. early onset familial alzheimer's disease can be attributed to mutations in one of three genes: those encoding amyloid-beta precursor protein (app) and presenilins psen1 and psen2. most mutations in the app and presenilin genes increase the production of a small protein called amyloid beta (aβ)42, which is the main component of amyloid plaques. some of the mutations merely alter the ratio between aβ42 and the other major forms—particularly aβ40—without increasing aβ42 levels. two other genes associated with autosomal dominant alzheimer's disease are abca7 and sorl1. most cases of alzheimer's are not inherited and are termed sporadic alzheimer's disease, in which environmental and genetic differences may act as risk factors. most cases of sporadic alzheimer's disease in contrast to familial alzheimer's disease are late-onset alzheimer's disease (load) developing after the age of 65 years. less than 5% of sporadic alzheimer's disease have an earlier onset. the strongest genetic risk factor for sporadic alzheimer's disease is apoeε4. apoeε4 is one of four alleles of apolipoprotein e (apoe). apoe plays a major role in lipid-binding proteins in lipoprotein particles and the epsilon4 allele disrupts this function. between 40 and 80% of people with alzheimer's disease possess at least one apoeε4 allele. the apoeε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes. like