Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a chronic neurodegenerative disease that usually starts slowly and worsens over time.[1][2] It is the cause of 60–70% of cases of dementia.[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 language, disorientation (including easily getting lost), mood swings, loss of motivation, not managing self care, and behavioural issues.[1][2] As a person's condition declines, they often withdraw from family and society.[1] Gradually, bodily functions are lost, ultimately leading to death.[10] Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.[7][11]

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.[4] Other risk factors include a history of head injuries, depression, or hypertension.[1] The disease process is associated with plaques and tangles in the brain.[4] 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] Initial symptoms are often mistaken for normal ageing.[1] Examination of brain tissue is needed for a definite diagnosis.[4] Mental and physical exercise, and avoiding obesity may decrease the risk of AD; however, evidence to support these recommendations is not strong.[4][12] There are no medications or supplements that have been shown to decrease risk.[13]

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.[14] Exercise programmes may be beneficial with respect to activities of daily living and can potentially improve outcomes.[15] Behavioural problems or psychosis due to dementia are often treated with antipsychotics, but this is not usually recommended, as there is little benefit with an increased risk of early death.[16][17]

In 2015, there were approximately 29.8 million people worldwide with AD.[2][8] It most often begins in people over 65years of age, although 4% to 5% of cases are early-onset Alzheimer's which begin before this.[3] It affects about 6% of people 65 years and older.[1] In 2015, dementia resulted in about 1.9 million deaths.[9] It was first described by, and later named after, German psychiatrist and pathologist Alois Alzheimer in 1906.[18]  In developed countries, AD is one of the most financially costly diseases.[19][20]

Signs and symptoms

Stages of Alzheimer's disease[21]

Effects of ageing on memory but not AD
Forgetting things occasionally
Misplacing items sometimes
Minor short-term memory loss
Not remembering exact details
Early stage Alzheimer's
Not remembering episodes of forgetfulness
Forgets names of family or friends
Changes may only be noticed by close friends or relatives
Some confusion in situations outside the familiar
Middle stage Alzheimer's
Greater difficulty remembering recently learned information
Deepening confusion in many circumstances
Problems with sleep
Trouble determining their location
Late stage Alzheimer's
Poor ability to think
Problems speaking
Repeats same conversations
More abusive, anxious, or paranoid

The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment.
Pre-dementia
The first symptoms are often mistakenly attributed to ageing or stress.[22] Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfils the clinical criteria for diagnosis of AD.[23] These early symptoms can affect the most complex activities of daily living.[24] 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.[23][25]
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.[23] Apathy can be observed at this stage, and remains the most persistent neuropsychiatric symptom throughout the course of the disease.[26] Depressive symptoms, irritability and reduced awareness of subtle memory difficulties are also common.[27]
The preclinical stage of the disease has also been termed mild cognitive impairment (MCI).[25] 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.[28]
Early
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.[29] 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 or how to drink from a glass) are affected to a lesser degree than new facts or memories.[30][31]
Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency, leading to a general impoverishment of oral and written language.[29][32] In this stage, the person with Alzheimer's is usually capable of communicating basic ideas adequately.[29][32][33]  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.[29] 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.[29]
Moderate
Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living.[29] 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.[29][33] Complex motor sequences become less coordinated as time passes and AD progresses, so the risk of falling increases.[29] During this phase, memory problems worsen, and the person may fail to recognise close relatives.[29] Long-term memory, which was previously intact, becomes impaired.[29]
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.[29] Sundowning can also appear.[34] Approximately 30% of people with AD develop illusionary misidentifications and other delusional symptoms.[29] Subjects also lose insight of their disease process and limitations (anosognosia).[29] Urinary incontinence can develop.[29] 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.[29][35]
Advanced
During the final stages, the patient is completely dependent upon caregivers.[29] Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech.[29][33] 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.[29]
Cause
The cause for most Alzheimer's cases is still mostly unknown except for 1% to 5% of cases where genetic differences have been identified.[36][37] Several competing hypotheses exist trying to explain the cause of the disease.
Genetic
The genetic heritability of Alzheimer's disease (and memory components thereof), based on reviews of twin and family studies, ranges from 49% to 79%.[38][39] Around 0.1% of the cases are familial forms of autosomal (not sex-linked) dominant inheritance, which have an onset before age 65.[40] 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.[41] 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.[42] Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels.[43][44]
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).[45][46] Between 40 and 80% of people with AD possess at least one APOEε4 allele.[46] The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes.[40] 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.[47][48] Early attempts to screen up to 400 candidate genes for association with late-onset sporadic AD (LOAD) resulted in a low yield.[40][41] More recent genome-wide association studies (GWAS) have found 19 areas in genes that appear to affect the risk.[49] These genes include: CASS4, CELF1, FERMT2, HLA-DRB5, INPP5D, MEF2C, NME8, PTK2B, SORL1, ZCWPW1, SlC24A4, CLU, PICALM, CR1, BIN1, MS4A, ABCA7, EPHA1, and CD2AP.[49]
Alleles in the TREM2 gene have been associated with a 3 to 5 times higher risk of developing Alzheimer's disease.[50][51] A suggested mechanism of action is that in some variants in TREM2 white blood cells in the brain are no longer able to control the amount of beta amyloid present. Many SNPs are associated with Alzheimer's with a 2018 study adding 30 SNPs by differentiating AD into 6 categories, including memory, language, visuospatial, and executive functioning.[52]
Cholinergic hypothesis
The oldest, on which most currently available drug therapies are based, is the cholinergic hypothesis,[53] 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.[54]
Amyloid hypothesis
In 1991, the amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease.[55][56] 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 AD by 40years of age.[57][58] Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. 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.[59] 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.[60]
An experimental vaccine was found to clear the amyloid plaques in early human trials, but it did not have any significant effect on dementia.[61] Researchers have been led to suspect non-plaque Aβ oligomers (aggregates of many monomers) as the primary pathogenic form of Aβ. 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.[62] One receptor for Aβ 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.[63]
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.[64] 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).[64] 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.
In early 2017, a trial of verubecestat, which inhibits the beta-secretase protein responsible for creating beta-amyloid protein was discontinued as an independent panel found "virtually no chance of finding a positive clinical effect".[65]
Tau hypothesis

The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade.[56] In this model, hyperphosphorylated tau begins to pair with other threads of tau. Eventually, they form neurofibrillary tangles inside nerve cell bodies.[66] When this occurs, the microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system.[67] This may result first in malfunctions in biochemical communication between neurons and later in the death of the cells.[68]
Other hypotheses
A neurovascular hypothesis has been proposed which states that poor functioning of the blood–brain barrier may be involved.[69]
The cellular homeostasis of biometals such as 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,[70] and their dysregulation may cause  oxidative stress that may contribute to the pathology.[71][72][73][74][75] The quality of some of these studies has been criticised,[76][77] and the link remains controversial.[78] The majority of researchers do not support a causal connection with aluminium.[77]
Smoking is a significant AD risk factor.[79] Systemic markers of the innate immune system are risk factors for late-onset AD.[80]
There is tentative evidence that exposure to air pollution may be a contributing factor to the development of Alzheimer's disease.[81]
Gum disease: An infection with Spirochetes (a bacterium) in gum disease may cause dementia and may be involved in the pathogenesis of Alzheimer's disease.[82] A fungal infection may also be a factor.[83]
One hypothesis posits that dysfunction of oligodendrocytes and their associated myelin during aging contributes to axon damage, which then causes amyloid production and tau hyper-phosphorylation as a side effect.[84][85]
Retrogenesis is a medical hypothesis about the development and progress of Alzheimer's disease proposed by Barry Reisberg in the 1980s.[86] The hypothesis is that just as the fetus goes through a process of neurodevelopment beginning with neurulation and ending with myelination, the brains of people with AD go through a reverse neurodegeneration process starting with demyelination and death of axons (white matter) and ending with the death of grey matter.[87] Likewise the hypothesis is, that as infants go through states of cognitive development, people with AD go through the reverse process of progressive cognitive impairment.[86] Reisberg developed the caregiving assessment tool known as "FAST" (Functional Assessment Staging Tool) which he says allows those caring for AD patients to identify the stages of disease progression and that provides advice about the kind of care needed at each stage.[86][88]
Pathophysiology

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.[89] Degeneration is also present in brainstem nuclei like the locus coeruleus.[90] 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.[91][92]
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD.[93] 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.[94] Lewy bodies are not rare in the brains of people with AD.[95]
Biochemistry

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.[96] Plaques are made up of small peptides, 39–43amino 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.[97][98] In Alzheimer's disease, gamma secretase and beta secretase act together in a proteolytic process which causes APP to be divided into smaller fragments.[99] 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.[93][100]
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.[101] Pathogenic tau can also cause neuronal death through transposable element dysregulation.[102]
Disease mechanism
Exactly how disturbances of production and aggregation of the beta-amyloid peptide give rise to the pathology of AD is not known.[103][104]
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).[105] 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.[106]
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.[107] There is increasing evidence of a strong interaction between the neurons and the immunological mechanisms in the brain. Obesity and systemic inflammation may interfere with immunological processes which promote disease progression.[108]
Alterations in the distribution of different neurotrophic factors and in the expression of their receptors such as the brain-derived neurotrophic factor (BDNF) have been described in AD.[109][110]
Diagnosis

Alzheimer's disease is usually diagnosed based on the person's medical history, history from relatives, and behavioural observations. The presence of characteristic neurological and neuropsychological features and the absence of alternative conditions is supportive.[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]
Assessment of intellectual functioning including memory testing can further characterise the state of the disease.[22] 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.[115]
Criteria
The National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA, now known as the Alzheimer's Association) established the most commonly used NINCDS-ADRDA Alzheimer's Criteria for diagnosis in 1984,[115] extensively updated in 2007.[116] 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.[117] Eight intellectual domains are most commonly impaired in AD—memory, language, perceptual skills, attention, motor skills, orientation, problem solving and executive 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.[118][119]
Techniques

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.[120][121] Neurological examination in early AD will usually provide normal results, except for obvious cognitive impairment, which may not differ from that resulting from other diseases processes, including other causes of dementia.
Further neurological examinations are crucial in the differential diagnosis of AD and other diseases.[22] 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.[122] A caregiver's viewpoint is particularly important, since a person with AD is commonly unaware of his own deficits.[123] Many times, families also have difficulties in the detection of initial dementia symptoms and may not communicate accurate information to a physician.[124]
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[22]—causes which may, in rare cases, be reversible.[125] It is common to perform thyroid function tests, assess B12, rule out syphilis, rule out metabolic problems (including tests for kidney function, electrolyte levels and for diabetes), assess levels of heavy metals (e.g. lead, mercury) and anaemia. (It is also necessary to rule out delirium).
Psychological tests for depression are employed, since depression can either be concurrent with AD (see Depression of Alzheimer disease), an early sign of cognitive impairment,[126] or even the cause.[127][128]
Due to low accuracy, the C-PIB-PET scan is not recommended to be used as an early diagnostic tool or for predicting the development of Alzheimer's disease when people show signs of mild cognitive impairment (MCI).[129] The use of ¹⁸F-FDG PET scans, as a single test, to identify people who may develop Alzheimer's disease is also not supported by evidence.[130]
Prevention

There is no definitive evidence to support that any particular measure is effective in preventing AD.[13] 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.[13]
Medication
Although cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,[131][132] statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease.[133][134][135]
Long-term usage of non-steroidal anti-inflammatory drugs (NSAIDs) were thought in 2007 to be associated with a reduced likelihood of developing AD.[136] Evidence also suggested the notion that NSAIDs could reduce inflammation related to amyloid plaques, but trials were suspended due to high adverse events.[13] No prevention trial has been completed.[13] They do not appear to be useful as a treatment, but as of 2011 were thought to be candidates as presymptomatic preventatives.[137] Hormone replacement therapy in menopause, although previously used, may increase the risk of dementia.[138]
Lifestyle
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.[139] 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.[139] Education delays the onset of AD syndrome without changing the duration of the disease.[140] Learning a second language even later in life seems to delay getting Alzheimer disease.[141]
Physical activity is also associated with a reduced risk of AD.[140] Physical exercise is associated with decreased rate of dementia.[142] Physical exercise is also effective in reducing symptom severity in those with Alzheimers.[143]
Diet

People who maintain a healthy, Japanese, or Mediterranean diet have a reduced risk of AD.[144] A Mediterranean diet may improve outcomes in those with the disease.[145] Those who eat a diet high in saturated fats and simple carbohydrates (mono- and disaccharide) have a higher risk.[146] The Mediterranean diet's beneficial cardiovascular effect has been proposed as the mechanism of action.[147]

Conclusions on dietary components have at times been difficult to ascertain as results have differed between population-based studies and randomised controlled trials.[144] There is limited evidence that light to moderate use of alcohol, particularly red wine, is associated with lower risk of AD.[144] There is tentative evidence that caffeine may be protective.[148] A number of foods high in flavonoids such as cocoa, red wine, and tea may decrease the risk of AD.[149][150]

Reviews on the use of vitamins and minerals have not found enough consistent evidence to recommend them. This includes vitamin A,[151][152] C,[153][154] the alpha-tocopherol form of vitamin E,[155] selenium,[156] zinc,[157][158] and folic acid with or without vitamin B12.[159] Evidence from one randomized controlled trial indicated that the alpha-tocopherol form of vitamin E may slow cognitive decline, this evidence was judged to be "moderate" in quality.[155] Trials examining folic acid (B9) and other B vitamins failed to show any significant association with cognitive decline.[160] Omega-3 fatty acid supplements from plants and fish, and dietary docosahexaenoic acid (DHA), do not appear to benefit people with mild to moderate Alzheimer's disease.[161][162]

Curcumin as of 2010 had not shown benefit in people even though there is tentative evidence in animals.[163] There was inconsistent and unconvincing evidence that ginkgo has any positive effect on cognitive impairment and dementia.[164] As of 2008 there was no concrete evidence that cannabinoids are effective in improving the symptoms of AD or dementia;[165] however, some research into endocannabinoids looked promising.[166]
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.
Medications

Five medications are currently used to treat the cognitive problems of AD: four are acetylcholinesterase inhibitors (tacrine, rivastigmine, galantamine and donepezil) and the other (memantine) is an NMDA receptor antagonist. The benefit from their use is small.[6][167][168] No medication has been clearly shown to delay or halt the progression of the disease.
Reduction in the activity of the cholinergic neurons is a well-known feature of Alzheimer's disease.[169] 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.[170] There is evidence for the efficacy of these medications in mild to moderate Alzheimer's disease,[171][168][167] and some evidence for their use in the advanced stage.[167] The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD.[172] 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, are mild to moderate in severity, and can be managed by slowly adjusting medication doses.[173] Less common secondary effects include muscle cramps, decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid production.[171]
Glutamate is an 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.[174] Memantine 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.[174][175] Memantine has been shown to have a small benefit in the treatment of Alzheimer's disease.[176] Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue.[177] The combination of memantine and donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".[178]
Atypical antipsychotics are modestly useful in reducing aggression and psychosis in people with Alzheimer's disease, but their advantages are offset by serious adverse effects, such as stroke, movement difficulties or cognitive decline.[179] When used in the long-term, they have been shown to associate with increased mortality.[180] Stopping antipsychotic use in this group of people appears to be safe.[181]
Huperzine A while promising, requires further evidence before its use can be recommended.[182]
Psychosocial intervention
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.[183]
Behavioural interventions attempt to identify and reduce the antecedents and consequences of problem behaviours. This approach has not shown success in improving overall functioning,[184] but can help to reduce some specific problem behaviours, such as incontinence.[185] There is a lack of high quality data on the effectiveness of these techniques in other behaviour problems such as wandering.[186][187] Music therapy is effective in reducing behavioural and psychological symptoms.[188]
Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration, also called snoezelen, and simulated presence therapy. A Cochrane review has found no evidence that this is effective.[189] Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired people adjust to their illness.[183] 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. A 2018 review of the effectiveness of RT found that effects were inconsistent, small in size and of doubtful clinical significance, and varied by setting.[190] 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 partial evidence indicating that SPT may reduce challenging behaviours.[191]
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 no evidence to support the usefulness of these therapies.[192][193]
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 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,[194][195] although in some studies these effects were transient and negative effects, such as frustration, have also been reported.[183]
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.[183] The efficacy of non-invasive brain stimulation and invasive brain stimulation in AD remains uncertain.[196]
Caregiving

Since Alzheimer's has no cure and it gradually renders people incapable of tending for their own needs, caregiving is essentially 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.[197][198] 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.[183][199][200] If eating becomes problematic, food will need to be prepared in smaller pieces or even pureed.[201] 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.[202][203] 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.[183]
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.[204][205] During the final stages of the disease, treatment is centred on relieving discomfort until death, often with the help of hospice.[206]
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. The symptoms 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, especially in the late stages of the disease.[29]
Life expectancy of people with AD is reduced.[207] Following diagnosis it typically ranges from three to ten years.[207]
Fewer than 3% of people live more than fourteen years.[208] 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.[209][210][211] 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.[212] Men have a less favourable survival prognosis than women.[208][213]
Pneumonia and dehydration are the most frequent immediate causes of death brought by AD, while cancer is a less frequent cause of death than in the general population.[213]

Epidemiology

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 any given time.
Regarding incidence, cohort longitudinal studies (studies where a disease-free population is followed over the years) provide rates between 10 and 15 per thousand person–years for all dementias and 5–8 for AD,[214][215] 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.[214][215] There are also sex differences in the incidence rates, women having a higher risk of developing AD particularly in the population older than 85.[215][216] In the United States, the risk of dying from Alzheimer's disease is 26% higher among the non-Hispanic white population than among the non-Hispanic black population, whereas the Hispanic population has a 30% lower risk than the non-Hispanic white population.[217]

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 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.[218] Prevalence rates in less developed regions are lower.[219] 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.[220] Other studies have reached similar conclusions.[219] 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 2050.[221]
History

The ancient Greek and Roman philosophers and physicians associated old age with increasing dementia.[18] It was not until 1901 that German psychiatrist Alois Alzheimer identified the first case of what became known as Alzheimer's disease, named after him, in a fifty-year-old woman he called Auguste D. He followed her case until she died in 1906, when he first reported publicly on it.[222] During the next five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease.[18] The disease was first described as a distinctive disease by Emil Kraepelin after suppressing some of the clinical (delusions and hallucinations) and pathological features (arteriosclerotic changes) contained in the original report of Auguste D.[223] He 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 on 15 July, 1910.[224]
For most of the 20th 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 that they had different causes.[225] This eventually led to the diagnosis of Alzheimer's disease independent of age.[226] 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 to describe those who were 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.[227]
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,[19][20] while their costs in other countries such as Argentina,[228] and South Korea,[229] are 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.[20] Numbers vary between studies but dementia costs worldwide have been calculated around $160billion,[230] while costs of Alzheimer's disease in the United States may be $100billion each year.[20]
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.[19] The cost of living at home is also very high,[19] especially when informal costs for the family, such as caregiving time and caregiver's lost earnings, are taken into account.[231]
Costs increase with dementia severity and the presence of behavioural disturbances,[232] and are related to the increased caregiving time required for the provision of physical care.[231] 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.[20]
Caregiving burden

The role of the main caregiver is often taken by the spouse or a close relative.[233] Alzheimer's disease is known for placing a great burden on caregivers which includes social, psychological, physical or economic aspects.[14][234][235] Home care is usually preferred by people with AD and their families.[236] This option also delays or eliminates the need for more professional and costly levels of care.[236][237] Nevertheless, two-thirds of nursing home residents have dementias.[183]
Dementia caregivers are subject to high rates of physical and mental disorders.[238] 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.[239][240] Regarding economic problems, family caregivers often give up time from work to spend 47hours 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.[231][233]
Cognitive behavioural therapy and the teaching of coping strategies either individually or in group have demonstrated their efficacy in improving caregivers' psychological health.[14][241]
Media

AD has been portrayed in films such as: Iris (2001), based on John Bayley's memoir of his wife Iris Murdoch;[242] The Notebook (2004), based on Nicholas Sparks' 1996 novel of the same name;[243] A Moment to Remember (2004);Thanmathra (2005);[244] Memories of Tomorrow (Ashita no Kioku) (2006), based on Hiroshi Ogiwara's novel of the same name;[245] Away from Her (2006), based on Alice Munro's short story "The Bear Came over the Mountain";[246] Still Alice (2014), about a Columbia University professor who has early onset Alzheimer's disease, based on Lisa Genova's 2007 novel of the same name and featuring Julianne Moore in the title role. 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.[247][248][249]
Research directions

Drugs
In the decade 2002–2012, 244 compounds were assessed in Phase I, Phase II, or Phase III trials, and only one of these (memantine) received FDA approval (though others were still in the pipeline).[250] Solanezumab failed to show effectiveness in patients who already had Alzheimer's symptoms.
One area of clinical research is focused on treating the underlying disease pathology. Reduction of beta-amyloid levels is a common target of compounds[251] (such as apomorphine) under investigation. Immunotherapy or vaccination for the amyloid protein is one treatment modality under study.[252] 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.[253] An example of such a vaccine under investigation was ACC-001,[254][255] although the trials were suspended in 2008.[256] Another similar agent is bapineuzumab, an antibody designed as identical to the naturally induced anti-amyloid antibody.[257] However, immunotherapeutic agents have been found to cause some concerning adverse drug reactions, such as amyloid-related imaging abnormalities.[258] Other approaches are neuroprotective agents, such as AL-108,[259] and metal-protein interaction attenuation agents, such as PBT2.[260] A TNFα receptor-blocking fusion protein, etanercept has showed encouraging results.[261]
In 2008, two separate clinical trials showed positive results in modifying the course of disease in mild to moderate AD with methylthioninium chloride, a drug that inhibits tau aggregation,[262][263] and dimebon, an antihistamine.[264]
The consecutive phase-III trial of dimebon failed to show positive effects in the primary and secondary endpoints.[265][266][267] Work with methylthioninium chloride showed that bioavailability of methylthioninium from the gut was affected by feeding and by stomach acidity, leading to unexpectedly variable dosing.[268] A new stabilised formulation, as the prodrug LMTX, is in phase-III trials (in 2014).[269]
Behavioral prevention
Preliminary research on the effects of meditation on retrieving memory and cognitive functions have been encouraging.[270]  A 2015 review suggests that mindfulness-based interventions may prevent or delay the onset of mild cognitive impairment and Alzheimer's disease.[271]
Possible transmission
Rare cases of possible transmission between people are being studied,[272] e.g. to growth hormone patients.[273]
Infections
The herpes simplex virus HSV-1 has been found in the same areas as amyloid plaques.[274] This suggested the possibility that AD could be treated or prevented with antiviral medication.[274][275] Studies of antivirals in cell cultures have shown promising results.[276]
Fungal infection of AD brain has also been described.[277]
This hypothesis was proposed by the microbiologist L. Carrasco when his group found statistical correlation between disseminated mycoses and AD.[278]
Further work revealed that fungal infection is present in different brain regions of AD patients, but not in the control individuals.[279]
[280]
A fungal infection explains the symptoms observed in AD patients. The slow progression of AD fits with the chronic nature of some systemic fungal infections, which can be asymptomatic and thus, unnoticed and untreated.[279]
The fungal hypotheses are also compatible with some other established AD hypotheses, like the amyloid hypothesis, that can be explained as an immune system response to an infection in the CNS,[281][282][283] as found by R. Moir and R. Tanzi in mouse and worm models of AD.
Imaging

Of the many medical imaging techniques available, single photon emission computed tomography (SPECT) appears to be superior in differentiating Alzheimer's disease from other types of dementia, and this has been shown to give a greater level of accuracy compared with mental testing and medical history analysis.[284] Advances have led to the proposal of new diagnostic criteria.[22][116]
PiB PET remains investigational, but a similar PET scanning radiopharmaceutical called florbetapir, containing the longer-lasting radionuclide fluorine-18, is a diagnostic tool in Alzheimer's disease.[285][286]
Amyloid imaging is likely to be used in conjunction with other markers rather than as an alternative.[287] Volumetric MRI can detect changes in the size of brain regions. Measuring those regions that atrophy during the progress of Alzheimer's disease is showing promise as a diagnostic indicator. It may prove less expensive than other imaging methods currently under study.[288]
In 2011 An FDA panel voted unanimously to recommend approval of florbetapir. The imaging agent can help to detect Alzheimer's brain plaques.[289] A negative scan indicates sparse or no plaques, which is not consistent with a diagnosis of AD.[290]
Early diagnosis
Emphasis in Alzheimer's research has been placed on diagnosing the condition before symptoms begin.[291] A number of biochemical tests have been developed to enable earlier detection. Some such tests involve the analysis of cerebrospinal fluid for beta-amyloid, total tau protein and phosphorylated tau181P protein concentrations.[292] Because drawing CSF can be painful, repeated draws are avoided. A blood test for circulatory miRNA and inflammatory biomarkers is a potential alternative indicator.[292]

Further reading

Library resources about
 Alzheimer's Disease

 at Curlie

What treatments exist for Alzheimer's disease?


The 1st Academy Awards ceremony, presented by the Academy of Motion Picture Arts and Sciences (AMPAS), honored the best films of 1927 and 1928 and took place on May 16, 1929 at a private dinner held at the Hollywood Roosevelt Hotel in Los Angeles, California. AMPAS president Douglas Fairbanks hosted the show. Tickets cost $5 (which would be $73 in 2018 considering inflation), 270 people attended the event and the presentation ceremony lasted 15 minutes. Awards were created by Louis B. Mayer, founder of Louis B. Mayer Pictures Corporation (at present merged into Metro-Goldwyn-Mayer). It is the only Academy Awards ceremony not to be broadcast either on radio or television. The radio broadcast was introduced the following year in 1930.
During the ceremony, the AMPAS presented Academy Awards, now known as the Oscars in 12 categories. Winners were announced three months before the live event. Some nominations were announced without reference to a specific film, such as for Ralph Hammeras and Nugent Slaughter, who received nominations in the now defunct category of Engineering Effects.[2] Unlike later ceremonies, an actor could be awarded for multiple works within a calendar year for the same category. Emil Jannings, for example, was given the Best Actor award for his work in both The Way of All Flesh and The Last Command. Also, Charlie Chaplin and Warner Brothers each received an Honorary Award.[3][4]
Major winners at the ceremony included 7th Heaven and Sunrise, which each received three awards, and Wings, receiving two awards. Among its honors, Sunrise won the award for Unique and Artistic Picture and Wings won the award for Outstanding Picture (now known as Best Picture). These two categories at the time were regarded equally as the top award of the night intended to honor different and important aspects of superior filmmaking. The next year, the Academy dropped the Unique and Artistic Picture award, and decided retroactively that the award won by Wings was the highest honor that could be awarded.[2]
Background
In 1927, the Academy of Motion Picture Arts and Sciences (AMPAS) was established by Louis B. Mayer, originator of Louis B. Mayer Pictures Corporation, which then would be joined into Metro-Goldwyn-Mayer (MGM). Mayer's purpose in creating the award was to unite the five branches of the film industry, including actors, directors, producers, technicians, and writers.[5] Mayer commented on the creation of the awards "I found that the best way to handle [filmmakers] was to hang medals all over them ... If I got them cups and awards, they'd kill them to produce what I wanted. That's why the Academy Award was created".[6] Mayer asked Cedric Gibbons, art director of MGM, to design an Academy Award trophy.[5][7] Nominees were notified through a telegram in February 1928.[5] In August 1928, Mayer contacted the Academy Central Board of Judges to decide winners.[5] However, according to the American director King Vidor, the voting for the Academy Award for Best Picture was in the hands of the AMPAS founders Douglas Fairbanks, Sid Grauman, Mayer, Mary Pickford, and Joseph Schenck.[8]
Ceremony
The ceremony was held on May 16, 1929[9][3][4][10] at the Hollywood Roosevelt Hotel, located in Los Angeles.[3] It consisted of a private dinner with 36 banquet tables,[11] where 270 people attended and tickets cost five dollars (equivalent to $72.96in 2018).[3] Actors and actresses arrived at the hotel in luxury vehicles, where many fans attended to encourage celebrities.[11] The ceremony was not broadcast on radio or television,[3] and was hosted by AMPAS director Fairbanks[9][3][4][12] during a 15-minute event.[10]
Winners and nominees
Winners were announced three months before the ceremony.[3][4][10] The recipients included: Emil Jannings, the inaugural first award recipient [3] for Best Actor (The Way of All Flesh and The Last Command);[4][10] Janet Gaynor for Best Actress (7th Heaven, Street Angel, and Sunrise: A Song of Two Humans); Frank Borzage for Best Director, Drama (7th Heaven); Lewis Milestone for Best Director, Comedy (Two Arabian Knights); and Wings for Best Picture (the most expensive film of its time).[9][2] Two presentations were made of a Special Award: Charlie Chaplin, a multiple nominee for one movie (Best Actor, Best Writer and Best Director, Comedy; all for The Circus) having been removed from the list so as to recognize his total contribution to the industry;[4] and Warner Brothers, an award for pioneering talking pictures (The Jazz Singer). Three categories were eliminated for subsequent presentations: Best Engineering Effects, Best Title Writing, and Best Unique and Artistic Quality of Production.[2] The larger film producers received the preponderance of awards: Fox Film Corporation, Metro-Goldwyn-Mayer, Paramount Pictures, Radio-Keith-Orpheum, and Warner Bros..[5]
Awards
Winners are listed first and indicated with double dagger

Honorary Awards
Charlie Chaplin
"For versatility and genius in acting, writing, directing and producing The Circus".[3]
Warner Brothers Production
"For producing The Jazz Singer, the pioneer outstanding talking picture, which has revolutionized the industry".[3]
Multiple nominations and awards

The following six films received multiple nominations:

The following three films received multiple awards:

Gallery
Academy Award winners – Gallery
Wings is the first film to win the Academy Award for Best Picture, which was at the time known as Outstanding Picture. Also won an award for the Best Engineering Effects[9]
Sunrise: A Song of Two Humans won the Academy Award for Best Unique and Artistic Picture, the only year that such a prize was awarded. The prize was intended to honor prestige art films separately from "commercial fare".[13]
Frank Borzage, Best Director, Dramatic Picture
Emil Jannings, Best Actor
Janet Gaynor, Best Actress
Charlie Chaplin, Honorary Award
Warner Brothers Production, Honorary Award. In top image First National Studios, Burbank, c. 1928.

See also
1927 in film
1928 in film

Bibliography

When was the first Academy Awards ceremony?


The red-eared slider (Trachemys scripta elegans), also known as the red-eared terrapin, is a semiaquatic turtle belonging to the family Emydidae. It is a subspecies of the pond slider. It is the most popular pet turtle in the United States and is also popular as a pet in the rest of the world.[2] It has, therefore, become the most commonly traded turtle in the world.[3] It is native to the southern United States and northern Mexico, but has become established in other places because of pet releases, and has become an invasive species in many areas, where it outcompetes native species. The red-eared slider is included in the list of the world's 100 most invasive species[4] published by the IUCN.
Name

The red-eared slider get its name from the small red stripe around its ears and from its ability to slide quickly off rocks and logs into the water. This species was previously known as Troost's turtle in honor of an American herpetologist Gerard Troost. Trachemys scripta troostii is now the scientific name for another subspecies, the Cumberland slider.
Taxonomy
The red-eared slider belongs to the order Testudines which contains about 250 turtle species. It is a subspecies of Trachemys scripta. It was previously classified under the name Chrysemys scripta elegans.
The species Trachemys scripta contains three subspecies: T. s. elegans (red-eared slider), T. s. scripta (yellow-bellied slider), and T. s. troostii (Cumberland slider).[5]
Description

The carapace of this species can reach more than 40cm (16in) in length, but the average length ranges from 15 to 20cm (6 to 8in).[6] The females of the species are usually larger than the males. They typically live between 20 and 30 years, although some individuals have lived for more than 40 years.[7] Their life expectancy is shorter when they are kept in captivity.[8] The quality of their living environment has a strong influence on their lifespans and well being.

These turtles are poikilotherms, meaning they are unable to regulate their body temperatures independently; they are completely dependent on the temperature of their environment.[2] For this reason, they need to sunbathe frequently to warm themselves and maintain their body temperatures.
The shell is divided into two sections: the upper or dorsal carapace, and the lower, ventral carapace or plastron.[2] The upper carapace consists of the vertebral scutes, which form the central, elevated portion; pleural scutes that are located around the vertebral scutes; and then the marginal scutes around the edge of the carapace. The rear marginal scutes are notched. The scutes are bony keratinous elements. The carapace is oval and flattened (especially in the male) and has a weak keel that is more pronounced in the young.[9] The color of the carapace changes depending on the age of the turtle. The carapace usually has a dark green background with light and dark, highly variable markings. In young or recently hatched turtles, it is leaf green and gets slightly darker as a turtle gets older, until it is a very dark green, and then turns a shade between brown and olive green. The plastron is always a light yellow with dark, paired, irregular markings in the centre of most scutes. The plastron is highly variable in pattern. The head, legs, and tail are green with fine, irregular, yellow lines. The whole shell is covered in these stripes and markings that aid in camouflaging an individual.

Turtles also have a complete skeletal system, with partially webbed feet that help them to swim and that can be withdrawn inside the carapace along with the head and tail. The red stripe on each side of the head distinguishes the red-eared slider from all other North American species and gives this species its name, as the stripe is located behind the eyes where their (external) ears would be. These stripes may lose their color over time.[8] Some individuals can also have a small mark of the same color on the top of their heads. The red-eared slider does not have a visible outer ear or an external auditory canal; instead, it relies on a middle ear entirely covered by a cartilaginous tympanic disc.[10]
The main internal organs of these reptiles are the lungs, heart, stomach, liver,  intestines, and the urinary bladder. A cloaca serves both excretory and reproductive functions.
Sexual dimorphism

Some dimorphism exists between males and females.[11]
Red-eared slider young look practically identical regardless of their sex, making it difficult to distinguish them. One useful method, however, is to inspect the markings under their carapace, which fade as the turtles age. It is much easier to distinguish the sex of adults, as the shells of mature males are smaller than those of females.[12] Male red-eared sliders reach sexual maturity when their carapaces' diameters measure 10cm (3.9in) and females reach maturity when their carapaces measure 15cm. Both male and females reach sexual maturity at five to six years.
The male is normally smaller than the female, although this parameter is sometimes difficult to apply as individuals being compared could be of different ages.
Males have longer claws on their front feet than the females; this helps them to hold on to a female during mating and is used during courtship displays.[13] The male's tail is thicker and longer. Typically, the cloacal opening of the female is at or under the rear edge of the carapace, while the male's opening occurs beyond the edge of the carapace. The male's plastron is slightly concave, while that of the female is completely flat. The male's concave plastron also helps to stabilize the male on the female's carapace during mating.[14] Older males can sometimes have a dark greyish-olive green melanistic coloration, with very subdued markings. The red stripe on the sides of the head may be difficult to see or be absent. The female's appearance is substantially the same throughout her life.
Distribution and habitat
The red-eared slider originated from the area around the Mississippi River and the Gulf of Mexico, in warm climates in the southeastern United States. Their native areas range from the southeast of Colorado to Virginia and Florida. In nature, they inhabit areas with a source of still, warm water, such as ponds, lakes, swamps, creeks, streams, or slow-flowing rivers. They live in areas of calm water where they are able to leave the water easily by climbing onto rocks or tree trunks so they can warm up in the sun. Individuals are often found sunbathing in a group or even on top of each other. They also require abundant aquatic plants, as these are
the adults' main food, although they are omnivores.[15] Turtles in the wild always remain close to water unless they are searching for a new habitat or when females leave the water to lay their eggs.
Owing to their popularity as pets, red-eared sliders have been released or escaped into the wild in many parts of the world.[16] The turtle is considered one of the world’s worst invasive species.[17] Feral populations are now found in Australia, Europe, South Africa, the Caribbean Islands, Israel, Bahrain, the Mariana Islands, Guam, and southeast and far-east Asia.[18][19] In Australia, it is illegal for members of the public to import, keep, trade, or release red-eared sliders, as they are regarded as an invasive species[20] - see below. Their import has been banned by the European Union[21] as well as specific EU member countries.[22] In 2015 Japan announced it was planning to ban the import of red-eared sliders, but it would probably not take effect until 2020.[23] Invasive red-eared sliders cause negative impacts in the ecosystems they occupy because they have certain advantages over the native populations, such as a lower age at maturity, higher fecundity rates, and larger body size, which gives them a competitive advantage at basking and nesting sites, as well as when exploiting food resources.[24] They also transmit diseases and displace the other turtle species with which they compete for food and breeding space.[25]
Behavior
Red-eared sliders are almost entirely aquatic, but as they are cold-blooded, they leave the water to sunbathe to regulate their temperature.

Hibernation
Red-eared sliders do not hibernate, but actually brumate; while they become less active, they do occasionally rise to the surface for food or air. Brumation can occur to varying degrees. In the wild, red-eared sliders brumate over the winter at the bottoms of ponds or shallow lakes. They generally become inactive in October, when temperatures fall below 10°C (50°F).[9] During this time, the turtles enter a state of sopor, during which they do not eat or defecate, they remain nearly motionless, and the frequency of their breathing falls.
Individuals usually brumate underwater, but they have also been found under banks and rocks, and in hollow stumps. In warmer winter climates, they can become active and come to the surface for basking. When the temperature begins to drop again, however, they quickly return to a brumation state. Sliders generally come up for food in early March to as late as the end of April.
During brumation, T. s. elegans can survive anaerobically for weeks, producing ATP from glycolysis. The turtle's metabolic rate drops dramatically, with heart rate and cardiac output dropping by 80% to minimise energy requirements.[26][27] The lactic acid produced is buffered by minerals in the shell, preventing acidosis.[28] Red-eared sliders kept captive indoors should not brumate.

Reproduction

Courtship and mating activities for red-eared sliders usually occur between March and July, and take place under water. During courtship, the male swims around the female and flutters or vibrates the back side of his long claws on and around her face and head, possibly to direct pheromones towards her.[29]  The female swims toward the male and, if she is receptive, sinks to the bottom for mating. If the female is not receptive, she may become aggressive towards the male. Courtship can last 45 minutes, but mating takes only 10 minutes.[25]

On occasion, a male may appear to be courting another male, and when kept in captivity may also show this behaviour towards other household pets. Between male turtles, it could be a sign of dominance and may preclude a fight. Young turtles may carry out the courtship dance before they reach sexual maturity at five years of age, but they are unable to mate.[30]
After mating, the female spends extra time basking to keep her eggs warm.[30] She may also have a change of diet, eating only certain foods, or not eating as much as she normally would. A female can lay between two and 30 eggs depending on body size and other factors.[18] One female can lay up to five clutches in the same year, and clutches are usually spaced 12 to 36 days apart.[31] The time between mating and egg-laying can be days or weeks. The actual egg fertilization takes place during the egg-laying. This process also permits the laying of fertile eggs the following season, as the sperm can remain viable and available in the female's body in the absence of mating. During the last weeks of gestation, the female spends less time in the water and smells and scratches at the ground, indicating she is searching for a suitable place to lay her eggs. The female excavates a hole, using her hind legs, and lays her eggs in it.[32]
Incubation takes 59 to 112 days.[18] Late-season hatchlings may spend the winter in the nest and emerge when the weather warms in the spring. Just prior to hatching, the egg contains 50% turtle and 50% egg sac. A new hatchling breaks open its egg with its egg tooth, which falls out about an hour after hatching. This egg tooth never grows back. Hatchlings may stay inside their eggshells after hatching for the first day or two. If they are forced to leave the eggshell before they are ready, they will return if possible. When a hatchling decides to leave the shell, it still has a small sac protruding from its plastron. The yolk sac is vital and provides nourishment while visible, and several days later it will have been absorbed into the turtle's belly. The sac must be absorbed, and does not fall off. The split must heal on its own before the turtle is able to swim. The time between the egg hatching and water entry is 21 days.
Damage to or inordinate motion of the protruding egg yolk, enough to allow air into the turtle's body, results in death. This is the main reason for marking the top of turtle eggs if their relocation is required for any reason. An egg turned upside down will eventually terminate the embryo's growth by the sac smothering the embryo. If it manages to reach term, the turtle will try to flip over with the yolk sac, which would allow air into the body cavity and cause death. The other fatal danger is water getting into the body cavity before the sac is absorbed completely and while the opening has not completely healed yet.
The sex of red-eared sliders is determined by the incubation temperature during critical phases of the embryos' development. Only males are produced when eggs are incubated at temperatures of 22–27°C (72–81°F), whereas females develop at warmer temperatures.[33] Colder temperatures result in the death of the embryos.
Red-eared sliders as pets

Red-eared slider turtles are the world’s most commonly traded reptile, due to their relatively low price, small size and easy maintenance.[34][35]  As with other turtles, tortoises, and box turtles, individuals that survive their first year or two can be expected to live generally around 30 years. But they are an infection risk, and when they mature they can inflict painful bites, which results in many being dumped into the wild with negative ecological, social and economic impacts.[36]
Infection risks and United States federal regulations on commercial distribution

Reptiles are asymptomatic (meaning they suffer no adverse side effects) carriers of bacteria of the genus Salmonella.[37] This has given rise to justifiable concerns given the many instances of infection of humans caused by the handling of turtles,[38] which has led to restrictions in the sale of red-eared sliders in the USA. A 1975 U.S. Food and Drug Administration (FDA) regulation bans the sale (for general commercial and public use) of both turtle eggs and turtles with a carapace length of less than 4in (10cm). This regulation comes under the Public Health Service Act, and is enforced by the FDA in cooperation with state and local health jurisdictions. The ban was enacted because of the public health impact of turtle-associated salmonellosis. Turtles and turtle eggs found to be offered for sale in violation of this provision are subject to destruction in accordance with FDA procedures. A fine of up to $1,001 and/or imprisonment for up to one year is the penalty for those who refuse to comply with a valid final demand for destruction of such turtles or their eggs.[39] Many stores and flea markets still sell small turtles due to an exception in the FDA regulation which allows turtles under 4in (10cm) to be sold "for bona fide scientific, educational, or exhibition purposes, other than use as pets."[40] As with many other animals and inanimate objects, the risk of Salmonella exposure can be reduced by following basic rules of cleanliness. Small children must be taught to wash their hands immediately after they finish playing with the turtle, feeding it, or changing its water.
US state law
Some states have other laws and regulations regarding possession of red-eared sliders because they can be an invasive species where they are not native and have been introduced through the pet trade. Now, it is illegal in Florida to sell any wild-type red-eared slider, as they interbreed with the local yellow-bellied slider population — Trachemys scripta scripta is another subspecies of pond sliders, and hybrids typically combine the markings of the two subspecies. However, unusual color varieties such as albino and pastel red-eared sliders, which are derived from captive breeding, are still allowed for sale.[41]

An invasive species in Australia
In Australia, breeding populations have been found in New South Wales and Queensland, and individual turtles have been found in the wild in Victoria, the Australian Capital Territory and Western Australia.[42]
Red-eared slider turtles are considered a significant threat to native turtle species – they mature more quickly, grow larger, produce more offspring and are more aggressive.[42] Numerous studies provide evidence that red-eared slider turtles can out-compete native turtles for food and nesting and basking sites.[43] Because red-eared slider turtles eat plants as well as animals, they could also have a negative impact on a range of native aquatic species, including rare frogs.[44] There is also a significant risk that red-eared slider turtles will transfer diseases and parasites to native reptile species.  There is evidence that a malaria-like parasite was spread to two wild turtle populations in Lane Cove River, Sydney.[45]
Social and economic costs are also likely to be substantial. The Queensland government has invested close to $1 million AUD in eradication programs to date.[42] As outlined in the foregoing section, the turtle may also have significant public health costs due to the impacts of turtle-associated salmonella on human health. Outbreaks in multiple states and fatalities in children, associated with handling salmonella-infected turtles, have been recorded in the USA.[46] Salmonella can also spread to humans when turtles contaminate drinking water.[47]
There have been varying degrees of action by state governments to date, ranging from ongoing eradication efforts by the Queensland government to very little action by the government of New South Wales.[48] Experts have ranked the species as high priority for management in Australia and are calling for a national prevention and eradication strategy, including a concerted education and compliance program to stop the illegal trade, possession and release of slider turtles.[49]
In popular culture
Within the second volume of the Tales of the Teenage Mutant Ninja Turtles, the popular comic book heroes were revealed as specimens of the red-eared slider. The popularity of the Turtles led to a craze for keeping them as pets in Great Britain, and subsequent ecological havoc as turtles were accidentally or deliberately released into the wild.[50]
See also
Yellow-bellied slider
Cumberland slider

Further reading
Rachel M. Bowden: "A Modified Yolk Biopsy Technique improves survivorship of turtle eggs". Cal State East Bay Press Sep./Oct. 2009, ISSN pp.611–615 (, p. 216, at Google Books)
Carl H. Ernst, Jeffrey E. Lovich: Turtles of the United States and Canada. Johns Hopkins University Press 2009, ISBN978-0-8018-9121-2, pp.444–470 (, p. 444, at Google Books)
James H. Harding: Amphibians and Reptiles of the Great Lakes Region. University of Michigan Press 1997, ISBN0-472-06628-5, pp.216–220 (, p. 216, at Google Books)
John B. Jensen, Carlos D. Camp, Whit Gibbons: Amphibians and Reptiles of Georgia. University of Georgia Press 2008, ISBN978-0-8203-3111-9, pp.500–502 (, p. 500, at Google Books)

How large does the red-eared slider get?