93-615: APOE may refer to: Apolipoprotein E , a main apoprotein of the chylomicron, also studied for its involvement in Alzheimer's disease risk Professional Oklahoma Educators , an organization in Oklahoma formerly known as the Association of Professional Oklahoma Educators or APOE Topics referred to by the same term [REDACTED] This disambiguation page lists articles associated with
186-645: A cluster with the apolipoprotein C1 ( APOC1 ) gene and the apolipoprotein C2 ( APOC2 ) gene. The APOE gene consists of four exons and three introns , totaling 3597 base pairs . APOE is transcriptionally activated by the liver X receptor (an important regulator of cholesterol , fatty acid , and glucose homeostasis ) and peroxisome proliferator-activated receptor γ, nuclear receptors that form heterodimers with retinoid X receptors . In melanocytic cells APOE gene expression may be regulated by MITF . Apoe-E
279-406: A proteolytic process which causes APP to be divided into smaller fragments. Although commonly researched as neuronal proteins, APP and its processing enzymes are abundantly expressed by other brain cells. One of these fragments gives rise to fibrils of amyloid beta, which then form clumps that deposit outside neurons in dense formations known as amyloid plaques. Excitatory neurons are known to be
372-711: A burden on caregivers . The pressures can include social, psychological, physical, and economic elements. Exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes. Behavioral problems or psychosis due to dementia are sometimes treated with antipsychotics , but this has an increased risk of early death. As of 2020, there were approximately 50 million people worldwide with Alzheimer's disease. It most often begins in people over 65 years of age, although up to 10% of cases are early-onset impacting those in their 30s to mid-60s. It affects about 6% of people 65 years and older, and women more often than men. The disease
465-470: A consequence of aging, the brains of people with Alzheimer's disease have a greater number of them in specific brain regions such as the temporal lobe . Lewy bodies are not rare in the brains of people with Alzheimer's disease. Alzheimer's disease has been identified as a protein misfolding disease , a proteopathy , caused by the accumulation of abnormally folded amyloid beta protein into amyloid plaques, and tau protein into neurofibrillary tangles in
558-456: A decline from a prior level of function and the diagnosis requires ruling out other common causes of neurocognitive decline. 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. On MRI or CT, Alzheimer's disease usually shows
651-550: A fire, reducing amyloid plaques may not affect the course of Alzheimer's disease." The role that the E4 variant carries can still be fully explained even in the absence of a valid amyloid hypothesis given the fact that reelin signaling emerges to be one of the key processes involved in Alzheimer's disease and the E4 variant is shown to interact with ApoER2 , one of the neuronal reelin receptors, thereby obstructing reelin signaling. Although 40–65% of AD patients have at least one copy of
744-404: A generalized or focal cortical atrophy, which may be asymmetric. Atrophy of the hippocampus is also commonly seen. Brain imaging commonly also shows cerebrovascular disease, most commonly previous strokes (small or large territory strokes), and this is thought to be a contributing cause of many cases of dementia (up to 46% cases of dementia also have cerebrovascular disease on imaging). FDG-PET scan
837-475: A high-fat diet. APOE knockout mice show marked attenuation of cerebral malaria and increased survival, as well as decreased sequestration of parasites and T cells within the brain, likely due to protection of the blood–brain barrier . Human studies have shown that the APOE2 polymorphism correlates with earlier infection, and APOE3/4 polymorphisms increase likelihood of severe malaria. Borrelia burgdorferi ,
930-846: A large exposed hydrophobic surface and interact with those in the N-terminal helix bundle domain through hydrogen bonds and salt-bridges. The C-terminal region also contains a low density lipoprotein receptor (LDLR)-binding site. APOE is polymorphic , with three major alleles (epsilon 2, epsilon 3, and epsilon 4): APOE-ε2 (cys112, cys158), APOE-ε3 (cys112, arg158), and APOE-ε4 (arg112, arg158). Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158, these differences alter APOE structure and function. There are several low-frequency polymorphisms of APOE. APOE5 comes in two subtypes E5f and E5s, based on migration rates. APOE5 E5f and APOE7 combined were found in 2.8% of Japanese males. APOE7
1023-409: 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. 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
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#17327647023161116-435: A mechanism of cell death in brain cells affected with tau tangles. Exactly how disturbances of production and aggregation of the beta-amyloid peptide give rise to the pathology of Alzheimer's disease is not known. 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
1209-420: A risk factor in the pathogenicity of Lyme disease. Click on genes, proteins and metabolites below to link to respective articles. Alzheimer%27s disease Alzheimer's disease ( AD ) is a neurodegenerative disease that usually starts slowly and progressively worsens, and is the cause of 60–70% of cases of dementia . The most common early symptom is difficulty in remembering recent events . As
1302-480: 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 Alzheimer's disease or a marker of an immunological response . 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. Alterations in
1395-561: Is APOEε4 . APOEε4 is one of four alleles of apolipoprotein E (APOE). APOE plays a major role in lipid-binding proteins in lipoprotein particles and the ε4 allele disrupts this function. Between 40% and 80% of people with Alzheimer's disease possess at least one APOEε4 allele. The APOEε4 allele increases the risk of the disease by three times in heterozygotes and by 15 times in homozygotes . Like many human diseases, environmental effects and genetic modifiers result in incomplete penetrance . For example, Nigerian Yoruba people do not show
1488-513: Is 299 amino acids long and contains multiple amphipathic α-helices . According to crystallography studies, a hinge region connects the N- and C-terminal regions of the protein. The N-terminal region ( residues 1–167) forms an anti-parallel four-helix bundle such that the non-polar sides face inside the protein. Meanwhile, the C-terminal domain (residues 206–299) contains three α-helices which form
1581-503: Is APOE4,4. Using genotype APOE3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0) and for white populations only, individuals with genotype APOE4,4 have an odds ratio of 14.9 of developing Alzheimer's disease. Individuals with the APOE3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (APOE2,4), have an odds ratio of 2.6. Persons with one copy each of
1674-488: 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. Likewise the hypothesis is, that as infants go through states of cognitive development , people with Alzheimer's disease go through
1767-419: Is a mutation of APOE3 with two lysine residues replacing glutamic acid residues at positions 244 and 245. E4 has been implicated in atherosclerosis , Alzheimer's disease , impaired cognitive function , reduced hippocampal volume, HIV , faster disease progression in multiple sclerosis , unfavorable outcome after traumatic brain injury , ischemic cerebrovascular disease , sleep apnea , both
1860-520: Is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases . It is encoded in humans by the gene APOE . Apo-E belongs to a family of fat-binding proteins called apolipoproteins . In the circulation, it is present as part of several classes of lipoprotein particles, including chylomicron remnants , VLDL , IDL , and some HDL . Apo-E interacts significantly with
1953-496: Is about 90% heritable. Familial Alzheimer's disease usually implies two or more persons affected in one or more generations. Early onset familial Alzheimer's disease can be attributed to mutations in one of three genes: those encoding amyloid-beta precursor protein (APP) and presenilins PSEN1 and PSEN2 . Most mutations in the APP and presenilin genes increase the production of a small protein called amyloid beta (Aβ)42, which
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#17327647023162046-529: Is available and can be examined histologically for senile plaques and neurofibrillary tangles. 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
2139-491: Is believed to occur when abnormal amounts of amyloid beta (Aβ), accumulating extracellularly as amyloid plaques and tau proteins , or intracellularly as neurofibrillary tangles , form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function. This altered protein clearance ability is age-related, regulated by brain cholesterol, and associated with other neurodegenerative diseases. The cause for most Alzheimer's cases
2232-565: Is characterized by build-ups of aggregates of the peptide beta-amyloid . Apolipoprotein E enhances proteolytic break-down of this peptide, both within and between cells. The isoform APOE-ε4 is not as effective as the others at promoting these reactions, resulting in increased vulnerability to AD in individuals with that gene variation. Recently, the amyloid hypothesis of Alzheimer's disease has been questioned, and an article in Science claimed that "Just as removing smoke does not extinguish
2325-435: Is complex and focuses on asymptomatic individuals; the latter two stages describe individuals experiencing symptoms. The core clinical criteria for MCI is used along with identification of biomarkers, predominantly those for neuronal injury (mainly tau-related) and amyloid beta deposition. The core clinical criteria itself rests on the presence of cognitive impairment without the presence of comorbidities. The third stage
2418-405: Is disrupted in Alzheimer's disease, though it remains unclear whether this is produced by or causes the changes in proteins. Smoking is a significant Alzheimer's disease risk factor. Systemic markers of the innate immune system are risk factors for late-onset Alzheimer's disease. Exposure to air pollution may be a contributing factor to the development of Alzheimer's disease. Retrogenesis
2511-526: Is divided into probable and possible AD dementia. In probable AD dementia there is steady impairment of cognition over time and a memory-related or non-memory-related cognitive dysfunction. In possible AD dementia, another causal disease such as cerebrovascular disease is present. Neuropsychological tests including cognitive tests such as the mini–mental state examination (MMSE), the Montreal Cognitive Assessment (MoCA) and
2604-547: Is frequently seen as a prodromal stage of Alzheimer's disease. Amnesic MCI has a greater than 90% likelihood of being associated with Alzheimer's. In people with Alzheimer's disease, the increasing impairment of learning and memory eventually leads to a definitive diagnosis. In a small percentage, difficulties with language, executive functions, perception ( agnosia ), or execution of movements ( apraxia ) are more prominent than memory problems. Alzheimer's disease does not affect all memory capacities equally. Older memories of
2697-406: 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. The first symptoms are often mistakenly attributed to aging or stress . Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills
2790-453: Is named after German psychiatrist and pathologist Alois Alzheimer , who first described it in 1906. Alzheimer's financial burden on society is large, with an estimated global annual cost of US$ 1 trillion. It is ranked as the seventh leading cause of death worldwide. Given the widespread impacts of Alzheimer's disease, both basic-science and health funders in many countries support Alzheimer's research at large scales. For example,
2883-432: Is needed for a definite diagnosis, but this can only take place after death . No treatments can stop or reverse its progression, though some may temporarily improve symptoms. A healthy diet, physical activity, and social engagement are generally beneficial in aging, and may help in reducing the risk of cognitive decline and Alzheimer's. Affected people become increasingly reliant on others for assistance, often placing
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2976-561: Is not required for the diagnosis but it is sometimes used when standard testing is unclear. FDG-PET shows a bilateral, asymetric, temporal and parietal reduced activity. Advanced imaging may predict conversion from prodromal stages (mild cognitive impairment) to Alzheimer's disease. FDA-approved radiopharmaceutical diagnostic agents used in PET for Alzheimer's disease are florbetapir (2012), flutemetamol (2013), florbetaben (2014), and flortaucipir (2020). Because many insurance companies in
3069-522: Is produced by macrophages and APOE secretion has been shown to be restricted to classical monocytes in PBMC, and the secretion of APOE by monocytes is down regulated by inflammatory cytokines and upregulated by TGF-beta. As of 2012, the E4 variant was the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups. However, the E4 variant does not correlate with risk in every population. Nigerian people have
3162-427: Is still mostly unknown, except for 1–2% of cases where deterministic genetic differences have been identified. Several competing hypotheses attempt to explain the underlying cause; the most predominant hypothesis is the amyloid beta (Aβ) hypothesis. The oldest hypothesis, on which most drug therapies are based, is the cholinergic hypothesis , which proposes that Alzheimer's disease is caused by reduced synthesis of
3255-513: 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. The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau as paired helical filaments . Eventually, they form neurofibrillary tangles inside neurons. When this occurs,
3348-522: Is the main component of amyloid plaques . Some of the mutations merely alter the ratio between Aβ42 and the other major forms—particularly Aβ40—without increasing Aβ42 levels in the brain. Two other genes associated with autosomal dominant Alzheimer's disease are ABCA7 and SORL1 . Alleles in the TREM2 gene have been associated with a three to five times higher risk of developing Alzheimer's disease. A Japanese pedigree of familial Alzheimer's disease
3441-419: Is three to twelve years. The cause of Alzheimer's disease is poorly understood. There are many environmental and genetic risk factors associated with its development. The strongest genetic risk factor is from an allele of apolipoprotein E . Other risk factors include a history of head injury , clinical depression , and high blood pressure . The progression of the disease is largely characterized by
3534-536: Is usually clinically diagnosed based on a person's medical history , observations from friends or relatives, and behavioral changes. The presence of characteristic neuropsychological changes with impairments in at least two cognitive domains that are severe enough to affect a person's functional abilities are required for the diagnosis. Domains that may be impaired include memory (most commonly impaired), language, executive function , visuospatial functioning, or other areas of cognition. The neurocognitive changes must be
3627-492: The brain , kidneys , and spleen . APOE synthesized in the liver associates with HDL which can then distribute it to newly formed VLDL or chylomicron particles to facilitate their eventual uptake by the liver. In the nervous system, non-neuronal cell types, most notably astroglia and microglia , are the primary producers of APOE, while neurons preferentially express the receptors for APOE. There are seven currently identified mammalian receptors for APOE which belong to
3720-428: The differential diagnosis of Alzheimer's disease and other diseases. 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 . A caregiver's viewpoint is particularly important, since a person with Alzheimer's disease is commonly unaware of their deficits . Many times, families have difficulties in
3813-468: The hippocampus . However, Alzheimer's disease may occur without neurofibrillary tangles in the neocortex . Plaques are dense, mostly insoluble deposits of beta-amyloid peptide and cellular material outside and around neurons . 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
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3906-423: The low density lipoprotein receptor gene family . Apo-E is the principal cholesterol carrier in the brain. Apo-E qualifies as a checkpoint inhibitor of the classical complement pathway by complex formation with activated C1q . Apolipoproteins are not unique to mammals. Many terrestrial and marine vertebrates have versions of them. It is believed that APOE arose via gene duplications of APOC1 before
3999-427: The low-density lipoprotein receptor (LDLR) , which is essential for the normal processing ( catabolism ) of triglyceride -rich lipoproteins. In peripheral tissues, Apo-E is primarily produced by the liver and macrophages , and mediates cholesterol metabolism. In the central nervous system , Apo-E is mainly produced by astrocytes and transports cholesterol to neurons via Apo-E receptors, which are members of
4092-610: The microtubules disintegrate, destroying the structure of the cell's cytoskeleton which collapses the neuron's transport system. 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 neuroinflammation . This chronic inflammation is also a feature of other neurodegenerative diseases including Parkinson's disease , and ALS . Spirochete infections have also been linked to dementia. DNA damages accumulate in Alzheimer's diseased brains; reactive oxygen species may be
4185-619: The temporal lobe and parietal lobe , and parts of the frontal cortex and cingulate gyrus . Degeneration is also present in brainstem nuclei particularly the locus coeruleus in the pons . Studies using MRI and PET have documented reductions in the size of specific brain regions in people with Alzheimer's disease as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults. Both Aβ plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those with Alzheimer's disease, especially in
4278-457: The 2 allele and the 3 allele (APOE2,3) have an odds ratio of 0.6. Persons with two copies of the 2 allele (APOE2,2) also have an odds ratio of 0.6. While ApoE4 has been found to greatly increase the odds that an individual will develop Alzheimer's, a 2002 study concluded, that in persons with any combination of APOE alleles, high serum total cholesterol and high blood pressure in mid-life are independent risk factors which together can nearly triple
4371-533: The APOE4 allele and Alzheimer's disease has been shown to be weaker in minority groups differently compared to their Caucasian counterparts. Hispanics/Latinos and African Americans who were homozygous for the APOE4 allele had 2.2 and 5.7 times the odds, respectively of developing Alzheimer's disease. The APOE4 allele has an even stronger effect in East Asian populations , with Japanese populations have 33 times
4464-614: The International Working Group criteria as revised in 2010. 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. 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
4557-521: The Mini-Cog are widely used to aid in diagnosis of the cognitive impairments in AD. These tests may not always be accurate, as they lack sensitivity to mild cognitive impairment, and can be biased by language or attention problems; more comprehensive test arrays are necessary for high reliability of results, particularly in the earliest stages of the disease. Further neurological examinations are crucial in
4650-751: The US National Institutes of Health program for Alzheimer's research, the National Plan to Address Alzheimer’s Disease, has a budget of US$ 3.98 billion for fiscal year 2026. In the European Union , the 2020 Horizon Europe research programme awarded over €570 million for dementia-related projects. The course of Alzheimer's is generally described in three stages, with a progressive pattern of cognitive and functional impairment . The three stages are described as early or mild, middle or moderate, and late or severe. The disease
4743-533: The United States do not cover this procedure, its use in clinical practice is largely limited to clinical trials as of 2018 . Assessment of intellectual functioning including memory testing can further characterise the state of the disease. 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
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#17327647023164836-572: The accumulation of malformed protein deposits in the cerebral cortex , called amyloid plaques and neurofibrillary tangles . These misfolded protein aggregates interfere with normal cell function, and over time lead to irreversible degeneration of neurons and loss of synaptic connections in the brain . A probable diagnosis is based on the history of the illness and cognitive testing , with medical imaging and blood tests to rule out other possible causes. Initial symptoms are often mistaken for normal brain aging . Examination of brain tissue
4929-431: The apolipoprotein ε4 isoform is more protective against cognitive decline than other isoforms in some cases, so caution is advised before making determinant statements about the influence of APOE polymorphisms on cognition, development of Alzheimer's disease, cardiovascular disease, telomere shortening, etc. Many of the studies cited that purport these adverse outcomes are from single studies that have not been replicated and
5022-437: The brain. Late-onset Alzheimer's is about 70% heritable . Genetic models in 2020 predict Alzheimer's disease with 90% accuracy. Most cases of Alzheimer's are not familial , and so they are termed sporadic Alzheimer's disease. Of the cases of sporadic Alzheimer's disease, most are classified as late onset where they are developed after the age of 65 years. The strongest genetic risk factor for sporadic Alzheimer's disease
5115-404: The brain. Plaques are made up of small peptides , 39–43 amino acids in length, called amyloid beta. Amyloid beta is a fragment from the larger amyloid-beta precursor protein (APP) a transmembrane protein that penetrates the cell's membrane . APP is critical to neuron growth, survival, and post-injury repair. In Alzheimer's disease, gamma secretase and beta secretase act together in
5208-498: The causative agent of Lyme disease , is a host-adapted pathogen that acquires environmental cholesterol to form glycolipids for use in cell membrane maintenance. In one experiment in 2015, mice engineered with apoE deficiency were infected with Borrelia spirochetes. The knockout mice suffered from an increased spirochete burden in joints, as well as inflamed ankles, when compared with wild-type mice. This study suggests that apoE deficiency (and potentially other hyperlipidemias) may be
5301-523: 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 Alzheimer's disease, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system. Pathogenic tau can also cause neuronal death through transposable element dysregulation. Necroptosis has also been reported as
5394-539: The clinical criteria for diagnosis of Alzheimer's disease. These early symptoms can affect the most complex activities of daily living . The most noticeable deficit is short term memory loss, which shows up as difficulty in remembering recently learned facts and inability to acquire new information. Subtle problems with the executive functions of attentiveness , planning , flexibility, and abstract thinking , or impairments in semantic memory (memory of meanings, and concept relationships) can also be symptomatic of
5487-478: The demyelinating disease, multiple sclerosis , and Alzheimer's disease have been reported. The association with celiac disease is unclear, with a 2019 study finding no increase in dementia overall in those with celiac disease while a 2018 review found an association with several types of dementia including Alzheimer's disease. Studies have shown a potential link between infection with certain viruses and developing Alzheimer's disease later in life. Notably,
5580-591: The detection of initial dementia symptoms and may not communicate accurate information to a physician. Supplemental testing can rule out other potentially treatable diagnoses and help avoid misdiagnoses. 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 ). MRI or CT scans might also be used to rule out other potential causes of
5673-438: The disease advances, symptoms can include problems with language , disorientation (including easily getting lost), mood swings , loss of motivation , self-neglect , and behavioral issues . As a person's condition declines, they often withdraw from family and society . Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis
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#17327647023165766-556: 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 Alzheimer's disease. 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. 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. AD
5859-423: The early stages of Alzheimer's disease. Apathy and depression can be seen at this stage, with apathy remaining as the most persistent symptom throughout the course of the disease. Mild cognitive impairment (MCI) is often found to be a transitional stage between normal aging and dementia . MCI can present with a variety of symptoms, and when memory loss is the predominant symptom, it is termed amnestic MCI and
5952-655: The evolutionarily conserved LDLR family. APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease . Defects in APOE result in familial dysbetalipoproteinemia aka type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron , VLDL and LDL . More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD), immunoregulation , and cognition . Though
6045-542: The exact mechanisms remain to be elucidated, isoform 4 of APOE, encoded by an APOE allele, has been associated with increased calcium ion levels and apoptosis following mechanical injury. In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing T cell proliferation, macrophage functioning regulation, lipid antigen presentation facilitation (by CD1 ) to natural killer T cell as well as modulation of inflammation and oxidation . APOE
6138-447: The extension and shortening of telomeres , reduced neurite outgrowth, and COVID-19 . However, E4 has also been associated with enhanced vitamin D and calcium status, higher fecundity , protection against early childhood infection and malnutrition , and decreased fetal , perinatal , and infant mortality. Much remains to be learned about the APOE isoforms, including the interaction of other protective genes. Indeed,
6231-462: The fact that people with trisomy 21 (Down syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of Alzheimer's disease by 40 years of age. A specific isoform of apolipoprotein, APOE4 , is a major genetic risk factor for Alzheimer's disease. While apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in
6324-462: The fish– tetrapod split ca. 400 million years ago. Proteins similar in function have been found in choanoflagellates , suggesting that they are a very old class of proteins predating the dawn of all living animals. The three major human alleles ( E4 , E3 , E2 ) arose after the primate–human split around 7.5 million years ago. These alleles are the by-product of non-synonymous mutations which led to changes in functionality. The first allele to emerge
6417-413: 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. The NIA-AA criteria are used mainly in research rather than in clinical assessments. They define AD through three major stages: preclinical, mild cognitive impairment (MCI), and Alzheimer's dementia. Diagnosis in the preclinical stage
6510-452: The fourth text revision of the DSM (DSM-IV-TR). The DSM-5 defines criteria for probable or possible AD for both major and mild neurocognitive disorder. Major or mild neurocognitive disorder must be present along with at least one cognitive deficit for a diagnosis of either probable or possible AD. For major neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if
6603-457: The highest observed frequency of the APOE4 allele in world populations, but AD is rare among them. This may be due to their low cholesterol levels. Caucasian and Japanese carriers of two E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. This may be caused by an interaction with amyloid . Alzheimer's disease
6696-412: The individual has genetic evidence of AD or if two or more acquired cognitive deficits, and a functional disability that is not from another disorder, are present. Otherwise, possible AD can be diagnosed as the diagnosis follows an atypical route. For mild neurocognitive disorder due to AD, probable Alzheimer's disease can be diagnosed if there is genetic evidence, whereas possible AD can be met if all of
6789-401: The major producers of amyloid beta that contribute to major extracellular plaque deposition. Alzheimer's disease 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
6882-399: The major source of this DNA damage. Sleep disturbances are seen as a possible risk factor for inflammation in Alzheimer's disease. Sleep disruption was previously only seen as a consequence of Alzheimer's disease, but as of 2020 , accumulating evidence suggests that this relationship may be bidirectional . The cellular homeostasis of biometals such as ionic copper, iron, and zinc
6975-492: The most cognitively demanding activities. Progressive deterioration eventually hinders independence, with subjects being unable to perform most common activities of daily living. Speech difficulties become evident due to an inability to recall vocabulary , which leads to frequent incorrect word substitutions ( paraphasias ). Reading and writing skills are also progressively lost. Complex motor sequences become less coordinated as time passes and Alzheimer's disease progresses, so
7068-445: The neurotransmitter acetylcholine . The loss of cholinergic neurons noted in the limbic system and cerebral cortex, is a key feature in the progression of Alzheimer's. The 1991 amyloid hypothesis postulated that extracellular amyloid beta (Aβ) deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21 , together with
7161-497: The odds compared to other populations. Caucasians who were homozygous for the allele had 12.5 times the odds. As a component of the lipoprotein lipid transport system, APOE facilitates the transport of lipids , fat-soluble vitamins , and cholesterol via the blood. It interacts with the LDL receptor to facilitate endocytosis of VLDL remnants. It is synthesized principally in the liver , but has also been found in other tissues such as
7254-582: The person from home care to other long-term care facilities . During the final stage, known as the late-stage or severe stage, there is complete dependence on caregivers. Language is reduced to simple phrases or even single words, eventually leading to complete loss of speech. Despite the loss of verbal language abilities, people can often understand and return emotional signals. Although aggressiveness can still be present, extreme apathy and exhaustion are much more common symptoms. People with Alzheimer's disease will ultimately not be able to perform even
7347-457: The person with Alzheimer's is usually capable of communicating basic ideas adequately. While performing fine motor tasks such as writing, drawing, or dressing, certain movement coordination and planning difficulties ( apraxia ) may be present; however, they are commonly unnoticed. As the disease progresses, people with Alzheimer's disease can often continue to perform many tasks independently; however, they may need assistance or supervision with
7440-450: The person's life ( episodic memory ), facts learned ( semantic memory ), and implicit memory (the memory of the body on how to do things, such as using a fork to eat or how to drink from a glass) are affected to a lesser degree than new facts or memories. Language problems are mainly characterised by a shrinking vocabulary and decreased word fluency , leading to a general impoverishment of oral and written language . In this stage,
7533-519: The relationship between dose of APOEε4 and incidence or age-of-onset for Alzheimer's disease seen in other human populations. 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. Less than 5% of sporadic Alzheimer's disease have an earlier onset, and early-onset Alzheimer's
7626-401: The research is based on unchecked assumptions about this isoform. As of 2007, there was no evidence that APOE polymorphisms influence cognition in younger age groups (other than possible increased episodic memory ability and neural efficiency in younger APOE4 age groups), nor that the APOE4 isoform places individuals at increased risk for any infectious disease. However, the association between
7719-594: The reverse process of progressive cognitive impairment . 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 hyperphosphorylation . An in vivo study employing genetic mouse models to simulate myelin dysfunction and amyloidosis further reveal that age-related myelin degradation increases sites of Aβ production and distracts microglia from Aβ plaques, with both mechanisms dually exacerbating amyloidosis. Additionally, comorbidities between
7812-809: The risk of falling increases. During this phase, memory problems worsen, and the person may fail to recognise close relatives. Long-term memory , which was previously intact, becomes impaired. Behavioral and neuropsychiatric changes become more prevalent. Common manifestations are wandering , irritability and emotional lability , leading to crying, outbursts of unpremeditated aggression , or resistance to caregiving. Sundowning can also appear. Approximately 30% of people with Alzheimer's disease develop illusionary misidentifications and other delusional symptoms. Subjects also lose insight of their disease process and limitations ( anosognosia ). Urinary incontinence can develop. These symptoms create stress for relatives and caregivers, which can be reduced by moving
7905-448: The risk that the individual will later develop AD. Projecting from their data, some researchers have suggested that lowering serum cholesterol levels may reduce a person's risk for Alzheimer's disease, even if they have two ApoE4 alleles, thus reducing the risk from nine or ten times the odds of getting AD down to just two times the odds. Women are more likely to develop AD than men across most ages and APOE genotypes. Premorbid women with
7998-625: The same substitutions were found in Denisovan APOE . About 220,000 years ago, a cysteine to arginine substitution took place at amino acid 112 (Cys112Arg) of the APOE4 gene, and this resulted in the E3 allele. Finally, 80,000 years ago, another arginine to cysteine substitution at amino acid 158 (Arg158Cys) of the APOE3 gene created the E2 allele. The gene, APOE , is mapped to chromosome 19 in
8091-427: The simplest tasks independently; muscle mass and mobility deteriorates to the point where they are bedridden and unable to feed themselves. The cause of death is usually an external factor, such as infection of pressure ulcers or pneumonia , not the disease itself. In some cases, there is a paradoxical lucidity immediately before death, where there is an unexpected recovery of mental clarity. Alzheimer's disease
8184-997: The title APOE . If an internal link led you here, you may wish to change the link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=APOE&oldid=1181776653 " Category : Disambiguation pages Hidden categories: Short description is different from Wikidata All article disambiguation pages All disambiguation pages Apolipoprotein E 1B68 , 1BZ4 , 1EA8 , 1GS9 , 1H7I , 1LE2 , 1LE4 , 1LPE , 1NFN , 1NFO , 1OEF , 1OEG , 1OR2 , 1OR3 , 2KC3 , 2KNY , 2L7B 348 11816 ENSG00000130203 ENSMUSG00000002985 P02649 P08226 NM_001302691 NM_000041 NM_001302688 NM_001302689 NM_001302690 NM_009696 NM_001305819 NM_001305843 NM_001305844 NP_000032 NP_001289617 NP_001289618 NP_001289619 NP_001289620 NP_001292748 NP_001292772 NP_001292773 NP_033826 Apolipoprotein E ( Apo-E )
8277-650: The toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis , induces programmed cell death ( apoptosis ). It is also known that A β 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. Iron dyshomeostasis is linked to disease progression, an iron-dependent form of regulated cell death called ferroptosis could be involved. Products of lipid peroxidation are also elevated in AD brain compared with controls. Various inflammatory processes and cytokines may also have
8370-461: The ε4 allele have significantly more neurological dysfunction than men. APOE-ε4 increases the risk not only for AD but also for dementia in pure alpha-synucleinopathies. The influence of APOE -ε4 on hippocampal atrophy was suggested to be more predominant early in the course of AD at milder stages prior to more widespread neurodegeneration. Knockout mice that lack the apolipoprotein-E gene (APOE ) develop extreme hypercholesterolemia when fed
8463-465: The ε4 allele, APOE4 is not a determinant of the disease. At least one-third of patients with AD are APOE4 negative and some APOE4 homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD. There is also evidence that the APOE2 allele may serve a protective role in AD. Thus, the genotype most at risk for Alzheimer's disease and at an earlier age
8556-468: Was E4. After the primate–human split, there were four amino acid changes in the human lineage, three of which had no effect on protein function (V174L, A18T, A135V). The fourth substitution (T61R) traded a threonine for an arginine altering the protein's functionality. This substitution occurred somewhere in the 6 million year gap between the primate–human split and the Denisovan –human split, since exactly
8649-493: Was found to be associated with a deletion mutation of codon 693 of APP. This mutation and its association with Alzheimer's disease was first reported in 2008, 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
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