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Symbol APOE contributors: mct/pgu - updated : 17-05-2017
HGNC name apolipoprotein E
HGNC id 613
Corresponding disease
AD2 Alzheimer disease associated with APOE4
APOE familial dysbetalipoproteinemia, hyperlipoproteinemia type III
ARMDS2 age related macular dystrophy, 2
SBHD sea-blue histiocyte disease
Location 19q13.32      Physical location : 45.409.038 - 45.412.649
Synonym name
  • apoprotein
  • apolipoprotein E3
  • Alzheimer disease 2 (APOE*E4-associated, late onset)
  • Synonym symbol(s) MGC1571, Apo-E, LPG, LDLCQ5, AD2, ApoE4
    TYPE functioning gene
    STRUCTURE 3.65 kb     4 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked Y status confirmed
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    - - - 34.15 299 - 2012 22615372
  • exhibits lower lipid binding ability than APOE4 as a consequence of a rearrangement involving the segment spanning AAs 261-272 in the C-terminal domain
  • APOE4 binds less strongly than APOE3 to HDL(3), consistent with apoE-lipid interactions being relatively unimportant for binding to HDL
  • stimulates neurite outgrowth
  • at residues 112 or 158, apoE3 has a cysteine at residue 112 and an arginine at residue 158
  • binds preferentially to HDL
  • - - - 34.15 299 primarily produced by astrocytes in the brain, but neurons can also produce APOE4 under stress conditions 2012 22615372
  • exhibits better lipid binding ability than APOE3 as a consequence of a rearrangement involving the segment spanning AAs 261-272
  • stronger lipid binding ability of APOE4 relative to that of APOE3
  • differs from the other two common isoforms (apoE2, apoE3) at residues 112 or 158, having arginines at both positions
  • may perturb mitochondrial respiratory function in the brain, rendering subjects with apoE4 more susceptible to AD neuropathology
  • detrimental effects of apoE4 on mitochondria can be mitigated by genetic and pharmacologic interference with apoE4 domain interaction
  • increases APP oligomers in the brain, which may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD
  • inhibits neurite outgrowth
  • should be considered a major gene, with semidominant inheritance, for late-onset AD
  • binds preferentially to very low-density lipoprotein (VLDL)
  • 4 - 1223 34.2 317 - 2012 22615372
    with two alternative stop codons
    - - 5515 - - liver 2012 22615372
    also called APOEAS2
    - - - - 219 parotis, kidney, liver, lung, thymus, small intestine 2012 22615372
  • also called APOEAS1
  • antisense transcript
  • 4 - 1316 - 343 - 2012 22615372
    4 - 1165 - 317 - 2012 22615372
    - - - 34.15 299 - 2012 22615372
  • at residues 112 or 158 having cysteines
  • protective for Alzheimer disease
  • 4 - 1249 - 343 - 2012 22615372
    4 - 1270 - 317 - 2012 22615372
    Type ubiquitous
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   highly Homo sapiens
    Endocrineadrenal gland   highly
    Lymphoid/Immunespleen   moderately
    Nervousbrain   predominantly Homo sapiens
    Reproductivefemale systemovary  moderately
    Respiratorylung   moderately
    Urinarykidney   highly
    Visualeyeretina  moderately
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Epithelialbarrier liningretinal pigment epithelium (RPE)  
    SystemCellPubmedSpeciesStageRna symbol
    Lymphoid/Immunemacrophage Homo sapiens
    Nervousastrocyte Homo sapiens
    Nervousneuron Homo sapiens
    cell lineage
    cell lines
    at STAGE
  • a N-terminal domain of interaction with the LDL receptor and heparin sulfate proteoglycan
  • a hinge region from the C-terminal lipid binding domain
  • an heparin binding region
  • conjugated GlycoP
    interspecies homolog to rattus Apoe (71.34 pc)
    homolog to murine Apoe (73.70 pc)
    intraspecies homolog to APOA4
  • APOA1/APOA4/APOE family
  • CATEGORY receptor membrane , transport carrier
        plasma membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    basic FUNCTION
  • clearance of chylomicrons, remnants and beta-VLDL from the plasma
  • modulates glutamate receptor function and synaptic plasticity by regulating apoE receptor recycling in neurons, with APOE3 stimulating and APOE4 inhibiting this process
  • in the nervous system, functions as a major carrier and distributor of cholesterol and other lipids, which are essential components of neuronal membranes and myelin sheaths
  • is required for maintenance of the dentate gyrus neural progenitor pool
  • APOE-induced intracellular APP degradation is mediated by the cholesterol efflux function of APOE, which lowers cellular cholesterol levels and subsequently facilitates the intracellular trafficking of APP to lysosomes for degradation
  • plays an important role in lipoprotein metabolism
  • role of APOE and COMT genes in prospective and retrospective memory traits
  • putative functional role of APOE in modulating myelin-related processes in the brain
  • major cholesterol carrier that supports lipid transport and injury repair in the brain
  • influences soluble APP metabolism not through direct binding to soluble APP in solution but through its actions with other interacting receptors/transporters and cell surfaces
  • APOE4 allele drives atrophy to the medial-temporal lobe region in AD
  • has an intrinsic role in pericyte mobility, which is vital in maintaining cerebrovascular function
  • role for APOE in lipid accumulation and adipogenic differentiation in adipose tissue
  • APOE is a critical determinants of brain phospholipid homeostasis and the APOE4 isoform is dysfunctional in this process
  • is an essential anti-atherosclerotic glycoprotein involved in lipid metabolism
  • impaired autophagy may play a role in mediating the pathological effects of APOE4 in AD
  • negative role of the APOE4 allele for cognitive performance in late life, while beneficial effects on cognition have been shown in young age
    metabolism lipid/lipoprotein
    signaling sensory transduction/vision
    fatty acid and sterol
    a component
  • constituent of several lipoproteins including chylomicrons, remnants, VLDL, IDL, some HDLs
    small molecule
  • binding to LDL receptor
  • binding with MYOC promoter SNP (increased intraocular pressure in primary open angle glaucoma
  • binding to heparin
  • APOE4 binds preferentially to very low-density lipoproteins (VLDLs), whereas APOE3 binds preferentially to high-density lipoproteins (HDLs), resulting in different plasma cholesterol levels for the two isoforms
  • APOE associated with APOB-carrying lipoproteins has an upregulatory role on ABCA1 expression, and induction of Sp1 phosphorylation is a mechanism by which APOE upregulates ABCA1 expression
  • mechanistic link between APOE-regulated cholesterol homeostasis and APP degradation
  • APP endocytic trafficking to lysosomes for degradation is a major APP clearance pathway that is differentially regulated by APOE isoforms
  • APOE/PLTP interactions can be modulated by the conformation and lipidation state of APOE
  • APOE regulates the endosomal formation of PMEL amyloid fibrils
  • robust synchronized induction of KLF4 and APOE expression during differentiation of monocytes to macrophages, and KLF4 up-regulates APOE gene in a dose-dependent manner
  • MYLIP is an E3 ubiquitin ligase that targets LDLR for degradation, is a critical determinant of brain APOE metabolism and APP plaque biogenesis
  • SFRS11 directly binds to the 3' UTR of LRP8 mRNA, as well as to the third exon of APOE mRNA, resulting in stabilization of these mRNAs, eventually deactivating JNK signaling
  • cell & other
    corresponding disease(s) APOE , ARMDS2 , SBHD , AD2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    APOE4-carriers with dementia of the Alzheimers' type, and memory decline and olfaction, compared to non-carriers, display a cortical atrophy pattern that is more focused on mediodisplay a cortical atrophy pattern that is more focused on mediotemporal lobe regions supporting olfactory and episodic memory functions
    constitutional     --low  
    depletion of endogenous APOE in adipocytes severely impairs lipid accumulation, which is associated with an inability to initiate differentiation (pMID: 26201081)
  • putative susceptibility factor (epsilon 4 allele) for agressive multiple sclerosis
  • susceptibility factor (epsilon 2/3/4 allele) for dementia (in old age)
  • susceptibility for AMD (age related macular dystrophy) (e2/e2 allele increased risk)
  • suceptibility (epsilon 2 allele) to frontotemporal dementia and to myocardial infarction
  • susceptibility to Alzheimer disease 2 (AD2)
  • to ischemic heart disease
  • to cerebral amyloid angiopathy and age-related cognitive decline during normal ageing
  • to Coronary Heart Disease (CHD)
  • Variant & Polymorphism SNP , other
  • (-219G) associated with increased optic nerve damage in primery open angle glaucoma
  • epsilon 2 allele by mother correlated with Smith-Lemli-Opitz severe form
  • ApoE4 mutation was associated with the increased risk of CHD, while ApoE2 allele had a decreased risk of CHD
  • combinations of SNPs in APOE and LPL identify subgroups of individuals at substantially increased risk of ischemic heart disease
  • APOE haplotypes common, found to be significantly associated with AMD, G-G-G-G-epsilon2, T-C-G-G-epsilon3 and T-G-A-G-epsilon4
  • risk estimate of developing AD for individuals with two copies of the apoE4 allele (&
  • 8764;2p100 of the population) is &
    8764;60p100 by the age of 85, and for those with one copy of the apoE4 allele (&
    8764;25p100 of the population) &
    8764;30p100, but the lifetime risk of AD for those with two copies of the apoE3 allele is &
    8764;10p100 by the age of 85
  • APOE4 allele is also associated with increased risk of cerebral amyloid angiopathy and age-related cognitive decline during normal ageing
  • Candidate gene
  • APOE genotyping may be helpful in diagnosing AD especially in patients presenting with atypical features or early age of onset of dementia
  • Therapy target
    pharmacological intervention with small molecules that disrupt apoE4 domain interaction is a potential therapeutic approach for apoE4-carrying AD subjects
  • apoE4 causes age- and Tau-dependent impairment of hilar GABAergic interneurons, leading to learning and memory deficits in mice (
  • young Apoe4 targeted replacement mice exhibit poor spatial learning and memory, with reduced dendritic spine density in the medial entorhinal cortex
  • hyper-neovascularization in the apoE4 mice might be driven by increased inflammation and the associated surge in Vegfa following injury
  • APOE4 reduces evoked hippocampal acetylcholine release in adult mice