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RAG Files/Alzheimer's Disease - Causes - 2.txt

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+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.[9] The loss of cholinergic neurons noted in the limbic system and cerebral cortex, is a key feature in the progression of Alzheimer's.[30] The 1991 amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease.[45][46] 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.[7] A specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for Alzheimer's disease.[10] 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.[47]

RAG Files/Alzheimer's Disease - Causes - 3.txt

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+Genetic
+Late onset
+Late-onset Alzheimer's is about 70% heritable.[48][49] Genetic models in 2020 predict Alzheimer's disease with 90% accuracy.[50] Most cases of Alzheimer's are not familial, and so they are termed sporadic Alzheimer's disease.[medical citation needed] Most cases of sporadic Alzheimer's disease are late onset, developing after the age of 65 years.[51]
+
+The strongest genetic risk factor for sporadic Alzheimer's disease is APOEε4.[14] APOEε4 is one of four alleles of apolipoprotein E (APOE). APOE plays a major role in lipid-binding proteins in lipoprotein particles and the ε4 allele disrupts this function.[52] Between 40 and 80% of people with Alzheimer's disease possess at least one APOEε4 allele.[53] The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes.[54] Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance. For example, Nigerian Yoruba people do not show the relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations.[55][56]

RAG Files/Alzheimer's Disease - Causes - 4.txt

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+Early onset
+Only 1–2% of Alzheimer's cases are inherited due to autosomal dominant effects, as Alzheimer's is highly polygenic. When the disease is caused by autosomal dominant variants, it is known as early onset familial Alzheimer's disease, which is rarer and has a faster rate of progression.[13] Less than 5% of sporadic Alzheimer's disease have an earlier onset,[13] and early-onset Alzheimer's is about 90% heritable.[48][49] FAD usually implies multiple persons affected in one or more generation.[medical citation needed][57]
+
+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.[31] 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.[58] Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels in the brain.[59] Two other genes associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1.[60]

RAG Files/Alzheimer's Disease - Causes - 5.txt

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+Alleles in the TREM2 gene have been associated with a three to five times higher risk of developing Alzheimer's disease.[61]
+
+A Japanese pedigree of familial Alzheimer's disease was found to be associated with a deletion mutation of codon 693 of APP.[62] This mutation and its association with Alzheimer's disease was first reported in 2008,[63] and is known as the Osaka mutation. Only homozygotes with this mutation have an increased risk of developing Alzheimer's disease. This mutation accelerates Aβ oligomerization but the proteins do not form the amyloid fibrils that aggregate into amyloid plaques, suggesting that it is the Aβ oligomerization rather than the fibrils that may be the cause of this disease. Mice expressing this mutation have all the usual pathologies of Alzheimer's disease.[64]

RAG Files/Alzheimer's Disease - Causes - 6.txt

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+Hypotheses
+Amyloid-beta and tau protein
+
+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.[46] In this model, hyperphosphorylated tau begins to pair with other threads of tau as paired helical filaments. Eventually, they form neurofibrillary tangles inside nerve cell bodies.[65] When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system.[66]
+
+A number of studies connect the misfolded amyloid beta and tau proteins associated with the pathology of Alzheimer's disease, as bringing about oxidative stress that leads to chronic inflammation.[67] Sustained inflammation (neuroinflammation) is also a feature of other neurodegenerative diseases including Parkinson's disease, and ALS.[68] Spirochete infections have also been linked to dementia.[9] DNA damages accumulate in AD brains; reactive oxygen species may be the major source of this DNA damage.[69]

RAG Files/Alzheimer's Disease - Causes - 7.txt

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+Sleep
+Sleep disturbances are seen as a possible risk factor for inflammation in Alzheimer's disease. Sleep problems have been seen as a consequence of Alzheimer's disease but studies suggest that they may instead be a causal factor. Sleep disturbances are thought to be linked to persistent inflammation.[70]
+
+Metal toxicity, smoking, neuroinflammation and air pollution
+The cellular homeostasis of biometals such as ionic copper, iron, and zinc is disrupted in Alzheimer's disease, though it remains unclear whether this is produced by or causes the changes in proteins.[9][71] Smoking is a significant Alzheimer's disease risk factor.[1] Systemic markers of the innate immune system are risk factors for late-onset Alzheimer's disease.[72] Exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.[9]
+

RAG Files/Alzheimer's Disease - Causes - 8.txt

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+Other hypotheses
+Retrogenesis is a medical hypothesis that just as the fetus goes through a process of neurodevelopment beginning with neurulation and ending with myelination, the brains of people with Alzheimer's disease go through a reverse neurodegeneration process starting with demyelination and death of axons (white matter) and ending with the death of grey matter.[73] Likewise the hypothesis is, that as infants go through states of cognitive development, people with Alzheimer's disease go through the reverse process of progressive cognitive impairment.[74]
+
+The association with celiac disease is unclear, with a 2019 study finding no increase in dementia overall in those with CD, while a 2018 review found an association with several types of dementia including Alzheimer's disease.[75][76]
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+According to one theory, dysfunction of oligodendrocytes and their associated myelin during aging contributes to axon damage, which in turn generates in amyloid production and tau hyper-phosphorylation.[77][78]
+
+Studies have shown a potential link between infection with certain viruses and developing Alzheimer's disease later in life.[79] Notably, a large scale study conducted on 6,245,282 patients has shown an increased risk of developing Alzheimer's disease following COVID-19 infection in cognitively normal individuals over 65.[80]

RAG Files/Alzheimer's Disease - Causes.txt

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+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.[40][41] This altered protein clearance ability is age-related, regulated by brain cholesterol,[42] and associated with other neurodegenerative diseases.[43][44]
+
+The cause for most Alzheimer's cases is still mostly unknown,[9] except for 1–2% of cases where deterministic genetic differences have been identified.[13] Several competing hypotheses attempt to explain the underlying cause; the most predominant hypothesis is the amyloid beta (Aβ) hypothesis.[9]
+

RAG Files/Alzheimer's Disease - Diagnosis - 2.txt

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+Criteria
+There are three sets of criteria for the clinical diagnoses of the spectrum of Alzheimer's disease: the 2013 fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5); the National Institute on Aging-Alzheimer's Association (NIA-AA) definition as revised in 2011; and the International Working Group criteria as revised in 2010.[31][116] Three broad time periods, which can span decades, define the progression of Alzheimer's disease from the preclinical phase, to mild cognitive impairment (MCI), followed by Alzheimer's disease dementia.[118]
+
+Eight intellectual domains are most commonly impaired in AD—memory, language, perceptual skills, attention, motor skills, orientation, problem solving and executive functional abilities, as listed in the fourth text revision of the DSM (DSM-IV-TR).[119]

RAG Files/Alzheimer's Disease - Diagnosis - 3.txt

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+The DSM-5 defines criteria for probable or possible Alzheimer's for both major and mild neurocognitive disorder.[120][121][110] Major or mild neurocognitive disorder must be present along with at least one cognitive deficit for a diagnosis of either probable or possible AD.[120][122] For major neurocognitive disorder due to Alzheimer's disease, probable Alzheimer's disease can be diagnosed if the individual has genetic evidence of Alzheimer's[123] or if two or more acquired cognitive deficits, and a functional disability that is not from another disorder, are present.[124] Otherwise, possible Alzheimer's disease can be diagnosed as the diagnosis follows an atypical route.[125] For mild neurocognitive disorder due to Alzheimer's, probable Alzheimer's disease can be diagnosed if there is genetic evidence, whereas possible Alzheimer's disease can be met if all of the following are present: no genetic evidence, decline in both learning and memory, two or more cognitive deficits, and a functional disability not from another disorder.[120][126]
+
+The NIA-AA criteria are used mainly in research rather than in clinical assessments.[127] They define Alzheimer's disease through three major stages: preclinical, mild cognitive impairment (MCI), and Alzheimer's dementia.[128][129] Diagnosis in the preclinical stage is complex and focuses on asymptomatic individuals;[129][130] the latter two stages describe individuals experiencing symptoms.[129] The core clinical criteria for MCI is used along with identification of biomarkers,[131] predominantly those for neuronal injury (mainly tau-related) and amyloid beta deposition.[127][129] The core clinical criteria itself rests on the presence of cognitive impairment[129] without the presence of comorbidities.[132][133] The third stage is divided into probable and possible Alzheimer's disease dementia.[133] In probable Alzheimer's disease dementia there is steady impairment of cognition over time and a memory-related or non-memory-related cognitive dysfunction.[133] In possible Alzheimer's disease dementia, another causal disease such as cerebrovascular disease is present.[133]
+

RAG Files/Alzheimer's Disease - Diagnosis - 4.txt

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+Techniques
+
+Cognitive tests such as the mini–mental state examination (MMSE) can help in the diagnosis of Alzheimer's disease. In this test instructions are given to copy drawings like the one shown, remember some words, read, and subtract numbers serially.
+Neuropsychological tests including cognitive tests such as the mini–mental state examination (MMSE), the Montreal Cognitive Assessment (MoCA) and the Mini-Cog are widely used to aid in diagnosis of the cognitive impairments in AD.[134] These tests may not always be accurate, as they lack sensitivity to mild cognitive impairment, and can be biased by language or attention problems;[134] more comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease.[135][136]
+

RAG Files/Alzheimer's Disease - Diagnosis - 5.txt

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+Further neurological examinations are crucial in the differential diagnosis of Alzheimer's disease and other diseases.[25] Interviews with family members are used in assessment; caregivers can supply important information on daily living abilities and on the decrease in the person's mental function.[137] A caregiver's viewpoint is particularly important, since a person with Alzheimer's disease is commonly unaware of their deficits.[138] Many times, families have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.[139]
+
+Supplemental testing can rule out other potentially treatable diagnoses and help avoid misdiagnoses.[140] Common supplemental tests include blood tests, thyroid function tests, as well as tests to assess vitamin B12 levels, rule out neurosyphilis and rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes).[140] MRI or CT scans might also be used to rule out other potential causes of the symptoms – including tumors or strokes.[134] Delirium and depression can be common among individuals and are important to rule out.[141]
+

RAG Files/Alzheimer's Disease - Diagnosis - 6.txt

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+Psychological tests for depression are used, since depression can either be concurrent with Alzheimer's disease (see Depression of Alzheimer disease), an early sign of cognitive impairment,[142] or even the cause.[143][144]
+
+Due to low accuracy, the C-PIB-PET scan is not recommended as an early diagnostic tool or for predicting the development of Alzheimer's disease when people show signs of mild cognitive impairment (MCI).[145] The use of 18F-FDG PET scans, as a single test, to identify people who may develop Alzheimer's disease is not supported by evidence.[146]

RAG Files/Alzheimer's Disease - Diagnosis.txt

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+Alzheimer's disease (AD) can only be definitively diagnosed with autopsy findings; in the absence of autopsy, clinical diagnoses of AD are "possible" or "probable", based on other findings.[108][109][110] Up to 23% of those clinically diagnosed with AD may be misdiagnosed and may have pathology suggestive of another condition with symptoms that mimic those of AD.[109]
+
+AD is usually clinically diagnosed based on the person's medical history, history from relatives, and behavioral observations. The presence of characteristic neurological and neuropsychological features and the absence of alternative conditions supports the diagnosis.[needs update][111][112] 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.[113] Moreover, it may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease.[114] FDA-approved radiopharmaceutical diagnostic agents used in PET for Alzheimer's disease are florbetapir (2012), flutemetamol (2013), florbetaben (2014), and flortaucipir (2020).[115] Because many insurance companies in the United States do not cover this procedure, its use in clinical practice is largely limited to clinical trials as of 2018.[116]
+
+Assessment of intellectual functioning including memory testing can further characterise the state of the disease.[1] Medical organizations have created diagnostic criteria to ease and standardise the diagnostic process for practising physicians. Definitive diagnosis can only be confirmed with post-mortem evaluations when brain material is available and can be examined histologically for senile plaques and neurofibrillary tangles.[116][117]

RAG Files/Alzheimer's Disease - Overview - 2.txt

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+The cause of Alzheimer's disease is poorly understood.[11] There are many environmental and genetic risk factors associated with its development. The strongest genetic risk factor is from an allele of APOE.[13][14] Other risk factors include a history of head injury, clinical depression, and high blood pressure.[1] The disease process is largely associated with amyloid plaques, neurofibrillary tangles, and loss of neuronal connections in the brain.[15] 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.[5][16] Initial symptoms are often mistaken for normal brain aging.[11] Examination of brain tissue is needed for a definite diagnosis, but this can only take place after death.[17] Good nutrition, physical activity, and engaging socially are known to be of benefit generally in aging, and may help in reducing the risk of cognitive decline and Alzheimer's.[15]

RAG Files/Alzheimer's Disease - Overview - 3.txt

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+No treatments can stop or reverse its progression, though some may temporarily improve symptoms.[2] Affected people become increasingly reliant on others for assistance, often placing a burden on caregivers.[18] The pressures can include social, psychological, physical, and economic elements.[18] Exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes.[19] 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.[20][21]

RAG Files/Alzheimer's Disease - Overview - 4.txt

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+As of 2020, there were approximately 50 million people worldwide with Alzheimer's disease.[9] It most often begins in people over 65 years of age, although up to 10% of cases are early-onset impacting those in their 30s to mid-60s.[17][4] It affects about 6% of people 65 years and older,[11] and women more often than men.[22] The disease is named after German psychiatrist and pathologist Alois Alzheimer, who first described it in 1906.[23] Alzheimer's financial burden on society is large, with an estimated global annual cost of US$1 trillion.[9] It is ranked as the seventh leading cause of death in the United States.[15]

RAG Files/Alzheimer's Disease - Overview.txt

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+Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens,[2] and is the cause of 60–70% of cases of dementia.[2][10] The most common early symptom is difficulty in remembering recent events.[1] 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.[2] As a person's condition declines, they often withdraw from family and society.[11] 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.[needs update][8][12]

RAG Files/Alzheimer's Disease - Prevention - 2.txt

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+Medication
+Cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and worsened course of AD.[149][150] The use of statins to lower cholesterol may be of benefit in Alzheimer's.[151] Antihypertensive and antidiabetic medications in individuals without overt cognitive impairment may decrease the risk of dementia by influencing cerebrovascular pathology.[1][152] More research is needed to examine the relationship with Alzheimer's disease specifically; clarification of the direct role medications play versus other concurrent lifestyle changes (diet, exercise, smoking) is needed.[1]
+
+Depression is associated with an increased risk for Alzheimer's disease; management with antidepressants may provide a preventative measure.[153]

RAG Files/Alzheimer's Disease - Prevention - 3.txt

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+Historically, long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs) were thought to be associated with a reduced likelihood of developing Alzheimer's disease as it reduces inflammation; however, NSAIDs do not appear to be useful as a treatment.[116] Additionally, because women have a higher incidence of Alzheimer's disease than men, it was once thought that estrogen deficiency during menopause was a risk factor. However, there is a lack of evidence to show that hormone replacement therapy (HRT) in menopause decreases risk of cognitive decline.[154]
+
+Plant-made metallochaperones could be a novel approach for the treatment of Alzheimer's disease.[155]

RAG Files/Alzheimer's Disease - Prevention - 4.txt

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+Lifestyle
+Further information: Neurobiological effects of physical exercise
+Certain lifestyle activities, such as physical and cognitive exercises, higher education and occupational attainment, cigarette smoking, stress, sleep, and the management of other comorbidities, including diabetes and hypertension, may affect the risk of developing Alzheimer's.[153]

RAG Files/Alzheimer's Disease - Prevention - 5.txt

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+Physical exercise is associated with a decreased rate of dementia,[156] and is effective in reducing symptom severity in those with AD.[157] Memory and cognitive functions can be improved with aerobic exercises including brisk walking three times weekly for forty minutes.[158] It may also induce neuroplasticity of the brain.[159] Participating in mental exercises, such as reading, crossword puzzles, and chess have shown a potential to be preventative.[153] Meeting the WHO recommendations for physical activity is associated with a lower risk of AD.[160]

RAG Files/Alzheimer's Disease - Prevention - 6.txt

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+Higher education and occupational attainment, and participation in leisure activities, contribute to a reduced risk of developing Alzheimer's,[161] or of delaying the onset of symptoms. 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.[161] Education delays the onset of Alzheimer's disease syndrome without changing the duration of the disease.[162]
+
+Cessation in smoking may reduce risk of developing Alzheimer's' disease, specifically in those who carry APOE ɛ4 allele.[163][153] The increased oxidative stress caused by smoking results in downstream inflammatory or neurodegenerative processes that may increase risk of developing AD.[164] Avoidance of smoking, counseling and pharmacotherapies to quit smoking are used, and avoidance of environmental tobacco smoke is recommended.[153]
+

RAG Files/Alzheimer's Disease - Prevention - 7.txt

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+Alzheimer's disease is associated with sleep disorders but the precise relationship is unclear.[165][166] It was once thought that as people get older, the risk of developing sleep disorders and AD independently increase, but research is examining whether sleep disorders may increase the prevalence of AD.[165] One theory is that the mechanisms to increase clearance of toxic substances, including Aβ, are active during sleep.[165][167] With decreased sleep, a person is increasing Aβ production and decreasing Aβ clearance, resulting in Aβ accumulation.[168][165][166] Receiving adequate sleep (approximately 7–8 hours) every night has become a potential lifestyle intervention to prevent the development of AD.[153]

RAG Files/Alzheimer's Disease - Prevention - 8.txt

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+Stress is a risk factor for the development of Alzheimer's.[153] The mechanism by which stress predisposes someone to development of Alzheimer's is unclear, but it is suggested that lifetime stressors may affect a person's epigenome, leading to an overexpression or under expression of specific genes.[169] Although the relationship of stress and Alzheimer's is unclear, strategies to reduce stress and relax the mind may be helpful strategies in preventing the progression or Alzheimer's disease.[170] Meditation, for instance, is a helpful lifestyle change to support cognition and well-being, though further research is needed to assess long-term effects.[159]

RAG Files/Alzheimer's Disease - Prevention.txt

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+There are no disease-modifying treatments available to cure Alzheimer's disease and because of this, AD research has focused on interventions to prevent the onset and progression.[147] There is no evidence that supports any particular measure in preventing Alzheimer's,[1] and studies of measures to prevent the onset or progression have produced inconsistent results. Epidemiological studies have proposed relationships between an individual's likelihood of developing AD and modifiable factors, such as medications, lifestyle, and diet. There are some challenges in determining whether interventions for Alzheimer's disease act as a primary prevention method, preventing the disease itself, or a secondary prevention method, identifying the early stages of the disease.[148] These challenges include duration of intervention, different stages of disease at which intervention begins, and lack of standardization of inclusion criteria regarding biomarkers specific for Alzheimer's disease.[148] Further research is needed to determine factors that can help prevent Alzheimer's disease.[148]

RAG Files/Alzheimer's Disease - Signs and Symptoms - Early Stage.txt

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+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.[32] 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.[33][34]
+
+Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, leading to a general impoverishment of oral and written language.[32][35] In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately.[32][35][36] 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.[32] 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.[32]

RAG Files/Alzheimer's Disease - Signs and Symptoms - First Symptoms.txt

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+First symptoms
+
+The first symptoms are often mistakenly attributed to aging or stress.[25] 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.[26] These early symptoms can affect the most complex activities of daily living.[27] 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.[26]
+
+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.[26] Apathy and depression can be seen at this stage, with apathy remaining as the most persistent symptom throughout the course of the disease.[28][29] 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.[30] Amnestic MCI has a greater than 90% likelihood of being associated with Alzheimer's.[31]

RAG Files/Alzheimer's Disease - Signs and Symptoms - Late Stage.txt

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+Late stage
+
+During the final stage, known as the late-stage or severe stage, there is complete dependence on caregivers.[15][24][32] Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech.[32][36] 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.[32] In some cases, there is a paradoxical lucidity immediately before death, where there is an unexpected recovery of mental clarity.[39]

RAG Files/Alzheimer's Disease - Signs and Symptoms - Middle Stage.txt

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+Middle stage
+Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living.[32] 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.[32][36] Complex motor sequences become less coordinated as time passes and Alzheimer's disease progresses, so the risk of falling increases.[32] During this phase, memory problems worsen, and the person may fail to recognise close relatives.[32] Long-term memory, which was previously intact, becomes impaired.[32]
+
+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.[32] Sundowning can also appear.[37] Approximately 30% of people with Alzheimer's disease develop illusionary misidentifications and other delusional symptoms.[32] Subjects also lose insight of their disease process and limitations (anosognosia).[32] Urinary incontinence can develop.[32] 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.[32][38]

RAG Files/Alzheimer's Disease - Signs and Symptoms.txt

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+The course of Alzheimer's is generally described in three stages, with a progressive pattern of cognitive and functional impairment.[24][17] The three stages are described as early or mild, middle or moderate, and late or severe.[24] 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.[15]