ア・リ・タンパク質E2

関: apo E2、apolipoprotein E2

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/29 16:38:29」(JST)

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Apolipoprotein E (APOE) is a class of apolipoprotein found in the chylomicron and Intermediate-density lipoprotein (IDLs) that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.^[1] In peripheral tissues, APOE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism in an isoform-dependent manner. In the central nervous system, APOE is mainly produced by astrocytes, and transports cholesterol to neurons via APOE receptors, which are members of the low density lipoprotein receptor gene family.^[2] This protein is involved in Alzheimer’s disease and cardiovascular disease.^[3]

Structure

Gene

The gene, APOE, is mapped to chromosome 19 in a cluster with Apolipoprotein C1 and the Apolipoprotein C2. 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.^[4] In melanocytic cells APOE gene expression may be regulated by MITF.^[5]

Protein

APOE 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 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.^[6]

Polymorphisms

APOE is polymorphic,^[7]^[8] with three major alleles: ApoE2 (cys112, cys158), ApoE3 (cys112, arg158), and ApoE4 (arg112, arg158).^[9]^[3]^[10] Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158,^[11]^[12]^[13] these differences alter APOE structure and function. These have physiological consequences:

E2 (rs7412) has an allele frequency of approximately 7 percent.^[14] This variant of the apoprotein binds poorly to cell surface receptors while E3 and E4 bind well.^[15] E2 is associated with both increased and decreased risk for atherosclerosis. Individuals with an E2/E2 combination may clear dietary fat slowly and be at greater risk for early vascular disease and the genetic disorder type III hyperlipoproteinemia—94.4% of such patients are E2/E2, while only ∼2% of E2/E2 develop the disease, so other environmental and genetic factors are likely to be involved (such as cholesterol in the diet and age).^[16]^[17]^[18] E2 has also been implicated in Parkinson's disease.^[19] E2 is no longer associated with Parkinson disease in a larger population association study.^[20]
E3 (rs429358) has an allele frequency of approximately 79 percent.^[14] It is considered the "neutral" Apo E genotype.
E4 has an allele frequency of approximately 14 percent.^[14] E4 has been implicated in atherosclerosis,^[21] Alzheimer's disease,^[22]^[23] impaired cognitive function,^[24]^[25] reduced hippocampal volume,^[25] HIV,^[26] faster disease progression in multiple sclerosis,^[27]^[28] unfavorable outcome after traumatic brain injury,^[29] ischemic cerebrovascular disease,^[30] sleep apnea,^[31]^[32] accelerated telomere shortening ^[33] and reduced neurite outgrowth.^[34] A notable advantage of the E4 allele (relative to E2 and E3) is a positive association with higher levels of vitamin D, which may help explain its prevalence despite its seeming complicity in various diseases or disorders.^[35]

However, there is much to be learned about these APOE isoforms, including the interaction of other potentially protective genetic polymorphisms, so caution is advised before making determinant statements about the influence of APOE polymorphisms; this is particularly true as it relates to how APOE isoforms influence cognition and the development of Alzheimer’s Disease. In addition, there is 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 is there evidence that the APOE4 isoform places individuals at increased risk for any infectious disease.^[36]

Function

APOE transports lipoproteins, fat-soluble vitamins, and cholesterol into the lymph system and then into the blood. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen.^[9] 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.^[37] There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved LDLR family.^[38]

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 remnants..^[1] 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.^[3]

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) ^[39] to natural killer T cell as well as modulation of inflammation and oxidation.^[40] APOE 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.^[41]

Clinical Significance

Alzheimer's disease

The E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups.^[42] Caucasian and Japanese carriers of 2 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. While the exact mechanism of how E4 causes such dramatic effects remains to be fully determined, evidence has been presented suggesting an interaction with amyloid.^[43] Alzheimer's disease 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.^[44]

The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance^[45] while working in the Roses lab at Duke University^[46] Linkage studies were followed by association analysis confirming the role of the ApoE4 allele as a strong genetic risk factor for AD.^[22]^[23]

Although 40-65% of AD patients have at least one copy of the ε4 allele, ApoE4 is not a determinant of the disease - at least a 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.^[47] There is also evidence that the ApoE2 allele may serve a protective role in AD.^[48] Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is ApoE 4,4. Using genotype ApoE 3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0), individuals with genotype ApoE4,4 have an odds ratio of 14.9 of developing Alzheimer's disease. Individuals with the ApoE 3,4 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 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.^[49]

Allele	ε2	ε3	ε4
Estimated worldwide human allele frequencies of ApoE * in Caucasian population^[49]
General Frequency	8.4%	77.9%	13.7%
AD Frequency	3.9%	59.4%	36.7%

Atherosclerosis

Knockout mice that lack the apolipoprotein-E gene (ApoE⁻/⁻) develop extreme hypercholesterolemia when fed a high-fat diet.^[50]

Interactions

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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|{{{bSize}}}px|alt=Statin Pathway edit]]

File:StatinPathway_WP430.png

Statin Pathway edit

^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

References

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^ "Margaret Pericak-Vance, Ph.D.". Miami Institute of Human Genomics.
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External links

Apolipoproteins E at the US National Library of Medicine Medical Subject Headings (MeSH)
apoe4.info - website for APOE-epsilon-4 carriers

UpToDate Contents

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English Journal

Apelin and its receptor APJ in cardiovascular diseases.

Yu XH1, Tang ZB2, Liu LJ3, Qian H3, Tang SL2, Zhang DW4, Tian GP5, Tang CK6.Author information 1Life Science Research Center, University of South China, Hengyang, Hunan 421001, China.2Department of Orthopedics, The First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, China.3Department of Clinical Medicine, Huaihua Medical College, Huaihua, Hunan 418000, China.4Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.5Department of Cardiovascular Medicine, The Second Affiliated Hospital, University of South China, Hengyang 421001, Hunan, China. Electronic address: pgtian555@hotmail.com.6Life Science Research Center, University of South China, Hengyang, Hunan 421001, China; Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, China. Electronic address: tangchaoke@qq.com.AbstractApelin is an adipokine that has been identified as an endogenous ligand for the orphan receptor APJ. Apelin and APJ are expressed in a diverse range of tissues with particular preponderance for the heart and vasculature. Apelin has powerful positive inotropic actions and causes endothelium- and nitric oxide-dependent vasodilatation. Growing evidence shows that apelin/APJ system functions as a critical mediator of cardiovascular homeostasis and is involved in the pathophysiology of cardiovascular diseases. Targeting apelin/APJ axis produces protection against cardiovascular diseases. In the current review we have summarized recent data concerning the role and therapeutic potential of apelin/APJ in several major cardiovascular diseases. An increased understanding of the cardiovascular actions of apelin/APJ system will help to develop novel therapeutic interventions for cardiovascular diseases.
Clinica chimica acta; international journal of clinical chemistry.Clin Chim Acta.2014 Jan 20;428:1-8. doi: 10.1016/j.cca.2013.09.001. Epub 2013 Sep 18.
Apelin is an adipokine that has been identified as an endogenous ligand for the orphan receptor APJ. Apelin and APJ are expressed in a diverse range of tissues with particular preponderance for the heart and vasculature. Apelin has powerful positive inotropic actions and causes endothelium- and nitr
PMID 24055369

Impact of the apolipoprotein E polymorphism, age and sex on neurogenesis in mice: Pathophysiological relevance for Alzheimer's disease?

Koutseff A1, Mittelhaeuser C1, Essabri K1, Auwerx J2, Meziane H3.Author information 1Institut Clinique de la Souris (ICS), Phenomin, Illkirch, France.2Laboratory of Integrative and Systems Physiology (LISP-NCEM), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.3Institut Clinique de la Souris (ICS), Phenomin, Illkirch, France. Electronic address: meziane@igbmc.fr.AbstractApolipoprotein E (ApoE) is found in three different forms in humans (ApoE2, ApoE3 and ApoE4), and ApoE polymorphism is recognized as a major risk factor for Alzheimer's disease (AD). ApoE is involved in lipid and cholesterol transport, cell repair, and amyloid-β deposition and certain studies suggest potential implications in neurogenesis. In this regard, we investigated the possible impact of the three different human ApoE isoforms on neurogenesis. We used ApoE knock-in mice of different ages and sex, and quantified newborn cells in the hippocampus by flow cytometry. Young adult ApoE4 mice (10-12 week-old) from both sexes displayed reduced neurogenesis compared with wild-types and the other genotypes. In addition, young adult ApoE2 female mice showed improved hippocampal progenitor cell proliferation. In older mice (1 year), hippocampal neurogenesis was globally decreased, particularly in females, and the difference between ApoE4 and the other genotypes observed in young animals disappeared for the two sexes, except for aged ApoE3 females. Indeed, a surprising protective effect of the ApoE3 genotype was observed in aged females. Our study highlights the role of ApoE in neurogenesis, and shows for the first time an early inequality between the ApoE genotypes. The reduced neurogenesis observed for the ApoE4 genotype and the improved results obtained in young ApoE2 females support the idea of a difference in the balance between neuronal birth and death modulated by the ApoE polymorphism in young animals. The maintenance of this balance and its modulation can influence pathophysiological mechanisms predisposing to neurodegenerative diseases like AD.
Brain research.Brain Res.2014 Jan 13;1542:32-40. doi: 10.1016/j.brainres.2013.10.003. Epub 2013 Oct 16.
Apolipoprotein E (ApoE) is found in three different forms in humans (ApoE2, ApoE3 and ApoE4), and ApoE polymorphism is recognized as a major risk factor for Alzheimer's disease (AD). ApoE is involved in lipid and cholesterol transport, cell repair, and amyloid-β deposition and certain studies sugge
PMID 24140109

APOBEC3 Deaminases Induce Hypermutation in Human Papillomavirus 16 DNA upon Beta Interferon Stimulation.

Wang Z, Wakae K, Kitamura K, Aoyama S, Liu G, Koura M, Monjurul AM, Kukimoto I, Muramatsu M.Author information Department of Molecular Genetics, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.AbstractApolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3) proteins are interferon (IFN)-inducible antiviral factors that counteract various viruses such as hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1) by inducing cytidine (C)-to-uracil (U) mutations in viral DNA and inhibiting reverse transcription. However, whether APOBEC3 proteins (A3s) can hypermutate human papillomavirus (HPV) viral DNA and exhibit antiviral activity in human keratinocyte remains unknown. Here we examined the involvement of A3s in the HPV life cycle using cervical keratinocyte W12 cells, which are derived from low-grade lesions and retain episomal HPV16 genomes in their nuclei. We focused on the viral E2 gene as a potential target for A3-mediated hypermutation because this gene is frequently found as a boundary sequence in integrated viral DNA. Treatment of W12 cells with beta interferon (IFN-β) increased expression levels of A3s such as A3A, A3F, and A3G and induced C-to-U conversions in the E2 gene in a manner depending on inhibition of uracil DNA glycosylase. Exogenous expression of A3A and A3G also induced E2 hypermutation in W12 cells. IFN-β-induced hypermutation was blocked by transfection of small interfering RNAs against A3G (and modestly by those against A3A). However, the HPV16 episome level was not affected by overexpression of A3A and A3G in W12 cells. This study demonstrates that endogenous A3s upregulated by IFN-β induce E2 hypermutation of HPV16 in cervical keratinocytes, and a pathogenic consequence of E2 hypermutation is discussed.
Journal of virology.J Virol.2014 Jan;88(2):1308-17. doi: 10.1128/JVI.03091-13. Epub 2013 Nov 13.
Apolipoprotein B mRNA-editing catalytic polypeptide 3 (APOBEC3) proteins are interferon (IFN)-inducible antiviral factors that counteract various viruses such as hepatitis B virus (HBV) and human immunodeficiency virus type 1 (HIV-1) by inducing cytidine (C)-to-uracil (U) mutations in viral DNA and
PMID 24227842

Japanese Journal

Prolonged High-Fat Feeding Enhances Aortic 18F-FDG and 99mTc-Annexin A5 Uptake in Apolipoprotein E-Deficient and Wild-Type C57BL/6J Mice

Zhao Yan,Kuge Yuji,Zhao Songji,Strauss H. William,Blankenberg Francis. G.,Tamaki Nagara
Journal of Nuclear Medicine 49(10), 1707-1714, 2008
… Here, we evaluated the aortic uptake of 18F-FDG and 99mTc-annexin A5 in apolipoprotein E-deficient (apoE2/2) and wild-type mice placed on high-fat diets. … Methods: Male apoE2/2 and wild-type (C57BL/6J) mice were maintained on high-fat diets after the age of 5 wk. … Results: No atherosclerotic lesions were found in wild-type mice regardless of the diet, whereas the lesion area progressively increased with age in apoE2/2 mice. …
NAID 120003118185

Apolipoprotein E Polymorphism Influences Lipid Phenotypes in Chinese Families With Familial Combined Hyperlipidemia

Pei Wei-Dong,Zhang Yan-Hong,Sun Yu-Hua,Gu Yu-Chun,Wang Yan-Fen,Zhang Chao-Yang,Zhang Jian,Liu Li-Sheng,Hui Ru-Tai,Liu Yu-Qing,Yang Yue-Jin
Circulation Journal 70(12), 1606-1610, 2006-11-20
… In men, the apoE2 (E3/2) subset indicated a decreased level of apoB and increased apoA1 compared with those in the apoE3 subset (p<0.05). …
NAID 110005518981

Related Pictures

APO E» redirige aquí. Para otras apoe2 1nfo: APOLIPOPROTEIN E2 (APOE2 Figure 1 : Possible mechanisms of APOE in File:ApoE2.jpg - Wikimedia Commons Oxidative Stress and Metabolic Syndrome apoE2, apoE3, and apoE4. LMT) A (sometimes referred to as ApoE2

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リンク元	「apolipoprotein E2」「アポリポタンパク質E2」
関連記事	「apo」

「apolipoprotein E2」

Apolipoprotein E
	PDB rendering based on 1b68.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1B68, 1BZ4, 1EA8, 1GS9, 1H7I, 1LE2, 1LE4, 1LPE, 1NFN, 1NFO, 1OEF, 1OEG, 1OR2, 1OR3, 2KC3, 2KNY, 2L7B
Identifiers
Symbols	APOE ; AD2; APO-E; LDLCQ5; LPG
External IDs	OMIM: 107741 MGI: 88057 HomoloGene: 30951 GeneCards: APOE Gene
Gene ontology
Molecular function	• beta-amyloid binding; • lipid transporter activity; • protein binding; • phospholipid binding; • heparin binding; • lipid binding; • cholesterol binding; • antioxidant activity; • cholesterol transporter activity; • identical protein binding; • protein homodimerization activity; • metal chelating activity; • tau protein binding; • low-density lipoprotein particle receptor binding; • phosphatidylcholine-sterol O-acyltransferase activator activity; • very-low-density lipoprotein particle receptor binding; • lipoprotein particle binding;
Cellular component	• extracellular region; • extracellular space; • nucleus; • cytoplasm; • early endosome; • endoplasmic reticulum; • Golgi apparatus; • plasma membrane; • membrane; • dendrite; • extracellular matrix; • very-low-density lipoprotein particle; • low-density lipoprotein particle; • intermediate-density lipoprotein particle; • high-density lipoprotein particle; • chylomicron; • neuronal cell body; • extracellular exosome; • endocytic vesicle lumen; • blood microparticle; • extracellular vesicle;
Biological process	• response to reactive oxygen species; • retinoid metabolic process; • negative regulation of endothelial cell proliferation; • response to dietary excess; • triglyceride metabolic process; • cholesterol biosynthetic process; • cholesterol catabolic process; • cellular calcium ion homeostasis; • receptor-mediated endocytosis; • cytoskeleton organization; • G-protein coupled receptor signaling pathway; • nitric oxide mediated signal transduction; • synaptic transmission, cholinergic; • phototransduction, visible light; • cholesterol metabolic process; • regulation of gene expression; • negative regulation of platelet activation; • positive regulation of cholesterol esterification; • positive regulation of cholesterol efflux; • long-chain fatty acid transport; • protein import; • virion assembly; • triglyceride catabolic process; • cGMP-mediated signaling; • negative regulation of blood coagulation; • regulation of axon extension; • positive regulation of cGMP biosynthetic process; • neuron projection regeneration; • regulation of Cdc42 protein signal transduction; • positive regulation of low-density lipoprotein particle receptor catabolic process; • cholesterol efflux; • phospholipid efflux; • very-low-density lipoprotein particle remodeling; • low-density lipoprotein particle remodeling; • high-density lipoprotein particle remodeling; • high-density lipoprotein particle assembly; • chylomicron remnant clearance; • high-density lipoprotein particle clearance; • very-low-density lipoprotein particle clearance; • lipoprotein metabolic process; • lipoprotein biosynthetic process; • lipoprotein catabolic process; • vasodilation; • cholesterol homeostasis; • negative regulation of MAP kinase activity; • negative regulation of neuron apoptotic process; • negative regulation of blood vessel endothelial cell migration; • reverse cholesterol transport; • small molecule metabolic process; • positive regulation by host of viral process; • negative regulation of cholesterol biosynthetic process; • positive regulation of lipid biosynthetic process; • intracellular transport; • regulation of neuronal synaptic plasticity; • artery morphogenesis; • negative regulation of inflammatory response; • positive regulation of nitric-oxide synthase activity; • positive regulation of membrane protein ectodomain proteolysis; • negative regulation of lipid biosynthetic process; • maintenance of location in cell; • fatty acid homeostasis; • positive regulation of dendritic spine development; • negative regulation of dendritic spine development; • negative regulation of cholesterol efflux; • alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate selective glutamate receptor clustering; • N-methyl-D-aspartate receptor clustering; • regulation of beta-amyloid clearance; • regulation of neuron death; • negative regulation of neuron death; • positive regulation of neuron death; • negative regulation of postsynaptic membrane organization; • positive regulation of postsynaptic membrane organization; • negative regulation of presynaptic membrane organization; • positive regulation of presynaptic membrane organization; • positive regulation of beta-amyloid formation; • negative regulation of beta-amyloid formation; • regulation of tau-protein kinase activity; • negative regulation of dendritic spine maintenance; • positive regulation of dendritic spine maintenance; • positive regulation of phospholipid efflux; • positive regulation of neurofibrillary tangle assembly; • negative regulation of phospholipid efflux; • negative regulation of lipid transport across blood brain barrier; • positive regulation of lipid transport across blood brain barrier;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;

　　[★]

ア・リ・タンパク質E2

関: apo E2、apoE2

「アポリポタンパク質E2」

　　[★]

英: apolipoprotein E2、apoE2、apo E2

「apo」

　　[★]

アポリポタンパク質、アポリポ蛋白質、アポリポタンパク、アポリポ蛋白、アポ

関: apolipoprotein

[WikiPathways-51] The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

[entrez-1] "Entrez Gene: APOE apolipoprotein E".

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[cardiogenetics-9] (editors), H.F. Baars, J.J. van der Smagt, P.A.F.M. Doevandans (2011). Clinical cardiogenetics. London: Springer. ISBN 9781849964715.

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[11] Online 'Mendelian Inheritance in Man' (OMIM) APOE3 isoform, hyperlipoproteinemia, type III, autosomal recessive -107741#0015

[12] Online 'Mendelian Inheritance in Man' (OMIM) APOE3 isoform, APOE, CYS112 and ARG158 -107741#0001

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[Meta-analysis-14] "Alzheimer Research Forum: Meta-Analyses of apolipoprotein E AD Association Studies".

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[pmid3283935-21] Mahley RW (Apr 1988). "Apolipoprotein E: cholesterol transport protein with expanding role in cell biology". Science 240 (4852): 622–30. doi:10.1126/science.3283935. PMID 3283935.

[pmid8346443-22] Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW et al. (Aug 1993). "Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families". Science 261 (5123): 921–3. doi:10.1126/science.8346443. PMID 8346443.

[pmid8446617-23] Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS et al. (Mar 1993). "Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease". Proceedings of the National Academy of Sciences of the United States of America 90 (5): 1977–81. doi:10.1073/pnas.90.5.1977. PMC 46003. PMID 8446617.

[24] Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C, Wright AF et al. (Aug 2002). "Cognitive change and the APOE epsilon 4 allele". Nature 418 (6901): 932. doi:10.1038/418932a. PMID 12198535.

[Cognitive_Impairment-25] Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC (Nov 2004). "Impact of APOE in mild cognitive impairment". Neurology 63 (10): 1898–901. doi:10.1212/01.wnl.0000144279.21502.b7. PMID 15557508.

[26] Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE et al. (Jun 2008). "Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression". Proceedings of the National Academy of Sciences of the United States of America 105 (25): 8718–23. doi:10.1073/pnas.0803526105. PMID 18562290.

[27] Chapman J, Vinokurov S, Achiron A, Karussis DM, Mitosek-Szewczyk K, Birnbaum M et al. (Feb 2001). "APOE genotype is a major predictor of long-term progression of disability in MS". Neurology 56 (3): 312–6. doi:10.1212/wnl.56.3.312. PMID 11171894.

[28] Schmidt S, Barcellos LF, DeSombre K, Rimmler JB, Lincoln RR, Bucher P et al. (Mar 2002). "Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis". American Journal of Human Genetics 70 (3): 708–17. doi:10.1086/339269. PMID 11836653.

[29] Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M, Tsenter J et al. (Jan 1999). "Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury". Neurology 52 (2): 244–8. doi:10.1212/wnl.52.2.244. PMID 9932938.

[30] McCarron MO, Delong D, Alberts MJ (Oct 1999). "APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis". Neurology 53 (6): 1308–11. doi:10.1212/wnl.53.6.1308. PMID 10522889.

[31] Kadotani H, Kadotani T, Young T, Peppard PE, Finn L, Colrain IM et al. (Jun 2001). "Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults". Jama 285 (22): 2888–90. doi:10.1001/jama.285.22.2888. PMID 11401610.

[32] Gottlieb DJ, DeStefano AL, Foley DJ, Mignot E, Redline S, Givelber RJ et al. (Aug 2004). "APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study". Neurology 63 (4): 664–8. doi:10.1212/01.wnl.0000134671.99649.32. PMID 15326239.

[pmid23418430-33] Jacobs EG, Kroenke C, Lin J, Epel ES, Kenna HA, Blackburn EH et al. (February 2013). "Accelerated cell aging in female APOE-ε4 carriers: implications for hormone therapy use". PloS One 8 (2): e54713. doi:10.1371/journal.pone.0054713. PMC 3572118. PMID 23418430.

[pmid18395206-34] Raber J (May 2008). "AR, apoE, and cognitive function". Hormones and Behavior 53 (5): 706–15. doi:10.1016/j.yhbeh.2008.02.012. PMC 2409114. PMID 18395206.

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[36] Mondadori CR, de Quervain DJ, Buchmann A, Mustovic H, Wollmer MA, Schmidt CF et al. (Aug 2007). "Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers". Cerebral Cortex 17 (8): 1934–47. doi:10.1093/cercor/bhl103. PMID 17077159.

[37] Zhang Z, Mu J, Li J, Li W, Song J (Jan 2013). "Aberrant apolipoprotein E expression and cognitive dysfunction in patients with poststroke depression". Genetic Testing and Molecular Biomarkers 17 (1): 47–51. doi:10.1089/gtmb.2012.0253. PMID 23171142.

[38] Rogers JT, Weeber EJ (Aug 2008). "Reelin and apoE actions on signal transduction, synaptic function and memory formation". Neuron Glia Biology 4 (3): 259–70. doi:10.1017/S1740925X09990184. PMID 19674510.

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[pmid20182542-40] Zhang HL, Wu J, Zhu J (2010). "The role of apolipoprotein E in Guillain-Barré syndrome and experimental autoimmune neuritis". Journal of Biomedicine & Biotechnology 2010: 357412. doi:10.1155/2010/357412. PMC 2825561. PMID 20182542.

[pmid24244577-41] Braesch-Andersen S, Paulie S, Smedman C, Mia S, Kumagai-Braesch M (2013). "ApoE production in human monocytes and its regulation by inflammatory cytokines". PloS One 8 (11): e79908. doi:10.1371/journal.pone.0079908. PMC 3828220. PMID 24244577.

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[pmid1625800-43] Wisniewski T, Frangione B (Feb 1992). "Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid". Neuroscience Letters 135 (2): 235–8. doi:10.1016/0304-3940(92)90444-C. PMID 1625800.

[Neuron-44] Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N et al. (Jun 2008). "ApoE promotes the proteolytic degradation of Abeta". Neuron (Cell Press) 58 (5): 681–93. doi:10.1016/j.neuron.2008.04.010. PMC 2493297. PMID 18549781. Lay summary – ScienceDaily (2008-06-13).

[urlMiami_Institute_of_Human_Genomics_-_People-45] "Margaret Pericak-Vance, Ph.D.". Miami Institute of Human Genomics.

[pmid_2035524-46] Pericak-Vance MA, Bebout JL, Gaskell PC, Yamaoka LH, Hung WY, Alberts MJ et al. (Jun 1991). "Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage". American Journal of Human Genetics 48 (6): 1034–50. PMC 1683100. PMID 2035524.

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[pmid7920638-48] Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC et al. (Jun 1994). "Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease". Nature Genetics 7 (2): 180–4. doi:10.1038/ng0694-180. PMID 7920638.

[ReferenceA-49] Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R et al. (1997). "Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium". Jama 278 (16): 1349–56. doi:10.1001/jama.1997.03550160069041. PMID 9343467.

[pmid20210786-50] McNeill E, Channon KM, Greaves DR (Jun 2010). "Inflammatory cell recruitment in cardiovascular disease: murine models and potential clinical applications". Clinical Science 118 (11): 641–55. doi:10.1042/CS20090488. PMID 20210786.

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apoE2