Apolipoprotein E: Difference between revisions

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{{Infobox_gene}}
{{Infobox_gene}}


'''Apolipoprotein E''' ('''ApoE''') is a class of proteins involved in the metabolism of fats in the body. It is important in [[Alzheimer's disease]] and [[cardiovascular disease]].<ref name="encyclopedia">{{cite book|last1=(ed.)|first1=Ian P. Stolerman|title=Encyclopedia of psychopharmacology|date=2010|publisher=Springer|location=Berlin|isbn=9783540686989|edition=Online-Ausg.}}</ref>
'''Apolipoprotein E''' ('''ApoE''') is a class of proteins involved in the metabolism of fats in the body. It is important in [[Alzheimer's disease]] and [[cardiovascular disease]].<ref name="encyclopedia">{{cite book | editor-first = Ian P. | editor-last = Stolerman | name-list-format = vanc | title = Encyclopedia of Psychopharmacology | date = 2010 | publisher = Springer | location = Berlin | isbn = 978-3540686989 | edition = Online }}</ref>


Lipoproteins are molecules composed of fats and proteins. Apolipoprotein E is a fat-binding protein ([[apolipoprotein]]) that is part of the [[chylomicron]] and [[intermediate density lipoprotein|Intermediate-density lipoprotein (IDLs)]]. These are essential for the normal processing ([[catabolism]]) of [[triglyceride]]-rich lipoproteins.<ref name="entrez">{{cite web | title = Entrez Gene: APOE apolipoprotein E| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=348| accessdate = }}</ref> In peripheral tissues, ApoE is primarily produced by the [[liver]] and [[macrophages]], and mediates [[cholesterol]] metabolism. 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]].<ref>{{cite journal | vauthors = Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G | title = Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy | journal = Nature Reviews. Neurology | volume = 9 | issue = 2 | pages = 106–18 | date = February 2013 | pmid = 23296339 | doi = 10.1038/nrneurol.2012.263 | pmc=3726719}}</ref> ApoE is the principal [[cholesterol]] carrier in the brain.<ref>{{cite journal | vauthors = Puglielli L, Tanzi RE, Kovacs DM | title = Alzheimer's disease: the cholesterol connection | language = en | journal = Nature Neuroscience | volume = 6 | issue = 4 | pages = 345–51 | date = April 2003 | pmid = 12658281 | doi = 10.1038/nn0403-345 }}</ref>
Lipoproteins are molecules composed of fats and proteins. Apolipoprotein E is a fat-binding protein ([[apolipoprotein]]) that is part of the [[chylomicron]] and [[intermediate density lipoprotein|intermediate-density lipoprotein (IDLs)]]. These are essential for the normal processing ([[catabolism]]) of [[triglyceride]]-rich lipoproteins.<ref name="entrez">{{cite web | title = Entrez Gene: APOE apolipoprotein E| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=348| accessdate = }}</ref> In peripheral tissues, ApoE is primarily produced by the [[liver]] and [[macrophages]], and mediates [[cholesterol]] metabolism. 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]].<ref>{{cite journal | vauthors = Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G | title = Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy | journal = Nature Reviews. Neurology | volume = 9 | issue = 2 | pages = 106–18 | date = February 2013 | pmid = 23296339 | doi = 10.1038/nrneurol.2012.263 | pmc=3726719}}</ref> ApoE is the principal [[cholesterol]] carrier in the brain.<ref>{{cite journal | vauthors = Puglielli L, Tanzi RE, Kovacs DM | title = Alzheimer's disease: the cholesterol connection | language = en | journal = Nature Neuroscience | volume = 6 | issue = 4 | pages = 345–51 | date = April 2003 | pmid = 12658281 | doi = 10.1038/nn0403-345 }}</ref>


==Structure==
==Structure==
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===Protein===
===Protein===
APOE is 299 [[amino acid]]s 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 bond]]s and salt-bridges. The C-terminal region also contains a [[low density lipoprotein receptor]] (LDLR)-binding site.<ref name="pmid25328986">{{cite journal | vauthors = Phillips MC | title = Apolipoprotein E isoforms and lipoprotein metabolism | journal = IUBMB Life | volume = 66 | issue = 9 | pages = 616–23 | date = September 2014 | pmid = 25328986 | doi = 10.1002/iub.1314 }}</ref>
APOE is 299 [[amino acid]]s 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 bond]]s and salt-bridges. The C-terminal region also contains a [[low density lipoprotein receptor]] (LDLR)-binding site.<ref name="pmid25328986">{{cite journal | vauthors = Phillips MC | title = Apolipoprotein E isoforms and lipoprotein metabolism | journal = IUBMB Life | volume = 66 | issue = 9 | pages = 616–23 | date = September 2014 | pmid = 25328986 | doi = 10.1002/iub.1314 }}</ref>


===Polymorphisms===
===Polymorphisms===
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''APOE'' is [[Polymorphism (biology)|polymorphic]],<ref name="pmid17092867">{{cite journal | vauthors = Singh PP, Singh M, Mastana SS | title = APOE distribution in world populations with new data from India and the UK | journal = Annals of Human Biology | volume = 33 | issue = 3 | pages = 279–308 | year = 2006 | pmid = 17092867 | doi = 10.1080/03014460600594513 }}</ref><ref name="10.1002/ajpa.21298">{{cite journal | vauthors = Eisenberg DT, Kuzawa CW, Hayes MG | title = Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history | journal = American Journal of Physical Anthropology | volume = 143 | issue = 1 | pages = 100–11 | date = September 2010 | pmid = 20734437 | doi = 10.1002/ajpa.21298 }}</ref>  with three major [[allele]]s: ''APOE-ε2'' (cys112, cys158), ''APOE-ε3'' (cys112, arg158), and ''APOE-ε4'' (arg112, arg158).<ref name="encyclopedia"/><ref name="cardiogenetics"/><ref>{{cite journal | vauthors = Ghebranious N, Ivacic L, Mallum J, Dokken C | title = Detection of ApoE E2, E3 and E4 alleles using MALDI-TOF mass spectrometry and the homogeneous mass-extend technology | journal = Nucleic Acids Research | volume = 33 | issue = 17 | pages = e149 | year = 2005 | pmid = 16204452 | pmc = 1243648 | doi = 10.1093/nar/gni155 }}</ref>  
''APOE'' is [[Polymorphism (biology)|polymorphic]],<ref name="pmid17092867">{{cite journal | vauthors = Singh PP, Singh M, Mastana SS | title = APOE distribution in world populations with new data from India and the UK | journal = Annals of Human Biology | volume = 33 | issue = 3 | pages = 279–308 | year = 2006 | pmid = 17092867 | doi = 10.1080/03014460600594513 }}</ref><ref name="10.1002/ajpa.21298">{{cite journal | vauthors = Eisenberg DT, Kuzawa CW, Hayes MG | title = Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history | journal = American Journal of Physical Anthropology | volume = 143 | issue = 1 | pages = 100–11 | date = September 2010 | pmid = 20734437 | doi = 10.1002/ajpa.21298 }}</ref>  with three major [[allele]]s (epsilon 2, epsilon 3, and epsilon 4): ''APOE-ε2'' (cys112, cys158), ''APOE-ε3'' (cys112, arg158), and ''APOE-ε4'' (arg112, arg158).<ref name="encyclopedia"/><ref name="cardiogenetics"/><ref>{{cite journal | vauthors = Ghebranious N, Ivacic L, Mallum J, Dokken C | title = Detection of ApoE E2, E3 and E4 alleles using MALDI-TOF mass spectrometry and the homogeneous mass-extend technology | journal = Nucleic Acids Research | volume = 33 | issue = 17 | pages = e149 | year = 2005 | pmid = 16204452 | pmc = 1243648 | doi = 10.1093/nar/gni155 }}</ref>  
Although these allelic forms differ from each other by only one or two [[amino acid]]s at positions 112 and 158,<ref>{{OMIM|107741#0015|APOE3 isoform, hyperlipoproteinemia, type III,  autosomal recessive}}</ref><ref>{{OMIM|107741#0001|APOE3 isoform, APOE, CYS112 and ARG158}}</ref><ref name="pmid16603077">{{cite journal | vauthors = Zuo L, van Dyck CH, Luo X, Kranzler HR, Yang BZ, Gelernter J | title = Variation at APOE and STH loci and Alzheimer's disease | journal = Behavioral and Brain Functions | volume = 2 | issue = 1 | pages = 13 | year = 2006 | pmid = 16603077 | pmc = 1526745 | doi = 10.1186/1744-9081-2-13 }}</ref> these differences alter APOE structure and function. These have physiological consequences:
Although these allelic forms differ from each other by only one or two [[amino acid]]s at positions 112 and 158,<ref>{{OMIM|107741#0015|APOE3 isoform, hyperlipoproteinemia, type III,  autosomal recessive}}</ref><ref>{{OMIM|107741#0001|APOE3 isoform, APOE, CYS112 and ARG158}}</ref><ref name="pmid16603077">{{cite journal | vauthors = Zuo L, van Dyck CH, Luo X, Kranzler HR, Yang BZ, Gelernter J | authorlink2=Christopher H. van Dyck | title = Variation at APOE and STH loci and Alzheimer's disease | journal = Behavioral and Brain Functions | volume = 2 | issue = 1 | pages = 13 | year = 2006 | pmid = 16603077 | pmc = 1526745 | doi = 10.1186/1744-9081-2-13 }}</ref> these differences alter APOE structure and function. These have physiological consequences:


* ε2 (rs7412-T, rs429358-T) has an [[allele frequency]] of approximately 7 percent.<ref name="Meta-analysis">{{cite web|title=Alzheimer Research Forum: Meta-Analyses of apolipoprotein E AD Association Studies |url=http://www.alzgene.org/meta.asp?geneID=83 |deadurl=yes |archiveurl=https://web.archive.org/web/20121124082912/http://www.alzgene.org/meta.asp?geneID=83 |archivedate=2012-11-24 }}</ref> This variant of the apoprotein binds poorly to cell surface receptors while E3 and E4 bind well.<ref>{{cite journal | vauthors = Weisgraber KH, Innerarity TL, Mahley RW | title = Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site | journal = The Journal of Biological Chemistry | volume = 257 | issue = 5 | pages = 2518–21 | date = March 1982 | pmid = 6277903 }}</ref> 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).<ref>{{cite journal | vauthors = Breslow JL, Zannis VI, SanGiacomo TR, Third JL, Tracy T, Glueck CJ | title = Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2 | journal = Journal of Lipid Research | volume = 23 | issue = 8 | pages = 1224–35 | date = November 1982 | pmid = 7175379 }}</ref><ref>{{cite journal | vauthors = Feussner G, Feussner V, Hoffmann MM, Lohrmann J, Wieland H, März W | title = Molecular basis of type III hyperlipoproteinemia in Germany | journal = Human Mutation | volume = 11 | issue = 6 | pages = 417–23 | year = 1998 | pmid = 9603433 | doi = 10.1002/(SICI)1098-1004(1998)11:6<417::AID-HUMU1>3.0.CO;2-5 }}</ref><ref>{{cite journal | vauthors = Civeira F, Pocoví M, Cenarro A, Casao E, Vilella E, Joven J, González J, Garcia-Otín AL, Ordovás JM | title = Apo E variants in patients with type III hyperlipoproteinemia | journal = Atherosclerosis | volume = 127 | issue = 2 | pages = 273–82 | date = December 1996 | pmid = 9125318 | doi = 10.1016/S0021-9150(96)05969-2 }}</ref> E2 has also been implicated in [[Parkinson's disease]],<ref>{{cite journal | vauthors = Huang X, Chen PC, Poole C | title = APOE-[epsilon]2 allele associated with higher prevalence of sporadic Parkinson disease | journal = Neurology | volume = 62 | issue = 12 | pages = 2198–202 | date = June 2004 | pmid = 15210882 | doi = 10.1212/01.wnl.0000130159.28215.6a }}</ref> but this finding was not replicated in a larger population association study.<ref>{{cite journal | vauthors = Federoff M, Jimenez-Rolando B, Nalls MA, Singleton AB | title = A large study reveals no association between APOE and Parkinson's disease | journal = Neurobiology of Disease | volume = 46 | issue = 2 | pages = 389–92 | date = May 2012 | pmid = 22349451 | pmc = 3323723 | doi = 10.1016/j.nbd.2012.02.002 }}</ref>
* ε2 (rs7412-T, rs429358-T) has an [[allele frequency]] of approximately 7 percent.<ref name="Meta-analysis">{{cite web|title=Alzheimer Research Forum: Meta-Analyses of apolipoprotein E AD Association Studies |url=http://www.alzgene.org/meta.asp?geneID=83 |deadurl=yes |archiveurl=https://web.archive.org/web/20121124082912/http://www.alzgene.org/meta.asp?geneID=83 |archivedate=2012-11-24 }}</ref> This variant of the apoprotein binds poorly to cell surface receptors while E3 and E4 bind well.<ref>{{cite journal | vauthors = Weisgraber KH, Innerarity TL, Mahley RW | title = Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site | journal = The Journal of Biological Chemistry | volume = 257 | issue = 5 | pages = 2518–21 | date = March 1982 | pmid = 6277903 }}</ref> 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).<ref>{{cite journal | vauthors = Breslow JL, Zannis VI, SanGiacomo TR, Third JL, Tracy T, Glueck CJ | title = Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2 | journal = Journal of Lipid Research | volume = 23 | issue = 8 | pages = 1224–35 | date = November 1982 | pmid = 7175379 }}</ref><ref>{{cite journal | vauthors = Feussner G, Feussner V, Hoffmann MM, Lohrmann J, Wieland H, März W | title = Molecular basis of type III hyperlipoproteinemia in Germany | journal = Human Mutation | volume = 11 | issue = 6 | pages = 417–23 | year = 1998 | pmid = 9603433 | doi = 10.1002/(SICI)1098-1004(1998)11:6<417::AID-HUMU1>3.0.CO;2-5 }}</ref><ref>{{cite journal | vauthors = Civeira F, Pocoví M, Cenarro A, Casao E, Vilella E, Joven J, González J, Garcia-Otín AL, Ordovás JM | title = Apo E variants in patients with type III hyperlipoproteinemia | journal = Atherosclerosis | volume = 127 | issue = 2 | pages = 273–82 | date = December 1996 | pmid = 9125318 | doi = 10.1016/S0021-9150(96)05969-2 }}</ref> E2 has also been implicated in [[Parkinson's disease]],<ref>{{cite journal | vauthors = Huang X, Chen PC, Poole C | title = APOE-[epsilon]2 allele associated with higher prevalence of sporadic Parkinson disease | journal = Neurology | volume = 62 | issue = 12 | pages = 2198–202 | date = June 2004 | pmid = 15210882 | doi = 10.1212/01.wnl.0000130159.28215.6a }}</ref> but this finding was not replicated in a larger population association study.<ref>{{cite journal | vauthors = Federoff M, Jimenez-Rolando B, Nalls MA, Singleton AB | title = A large study reveals no association between APOE and Parkinson's disease | journal = Neurobiology of Disease | volume = 46 | issue = 2 | pages = 389–92 | date = May 2012 | pmid = 22349451 | pmc = 3323723 | doi = 10.1016/j.nbd.2012.02.002 }}</ref>
* ε3 (rs7412-C, rs429358-T) has an allele frequency of approximately 79 percent.<ref name="Meta-analysis"/> It is considered the "neutral" Apo E genotype.
* ε3 (rs7412-C, rs429358-T) has an allele frequency of approximately 79 percent.<ref name="Meta-analysis"/> It is considered the "neutral" Apo E genotype.
* {{anchor|E4}}ε4 (rs7412-C, rs429358-C) has an allele frequency of approximately 14 percent.<ref name="Meta-analysis"/> E4 has been implicated in [[atherosclerosis]],<ref name="pmid3283935">{{cite journal | vauthors = Mahley RW | title = Apolipoprotein E: cholesterol transport protein with expanding role in cell biology | journal = Science | volume = 240 | issue = 4852 | pages = 622–30 | date = April 1988 | pmid = 3283935 | doi = 10.1126/science.3283935 }}</ref> [[Alzheimer's disease]],<ref name="pmid8346443">{{cite journal | vauthors = Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA | title = Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families | journal = Science | volume = 261 | issue = 5123 | pages = 921–3 | date = August 1993 | pmid = 8346443 | doi = 10.1126/science.8346443 }}</ref><ref name="pmid8446617">{{cite journal | vauthors = Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD | title = Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 5 | pages = 1977–81 | date = March 1993 | pmid = 8446617 | pmc = 46003 | doi = 10.1073/pnas.90.5.1977 }}</ref> impaired [[cognitive function]],<ref>{{cite journal | vauthors = Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C, Wright AF, Carothers A, Whalley LJ | title = Cognitive change and the APOE epsilon 4 allele | journal = Nature | volume = 418 | issue = 6901 | pages = 932 | date = August 2002 | pmid = 12198535 | doi = 10.1038/418932a }}</ref><ref name="Cognitive Impairment">{{cite journal | vauthors = Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC | title = Impact of APOE in mild cognitive impairment | journal = Neurology | volume = 63 | issue = 10 | pages = 1898–901 | date = November 2004 | pmid = 15557508 | doi = 10.1212/01.wnl.0000144279.21502.b7 }}</ref> reduced [[hippocampal]] volume,<ref name="Cognitive Impairment"/> [[HIV]],<ref>{{cite journal | vauthors = Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, Cavrois M, Huang Y, Mahley RW, Dolan MJ, McCune JM, Ahuja SK | title = Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 25 | pages = 8718–23 | date = June 2008 | pmid = 18562290 | doi = 10.1073/pnas.0803526105 | pmc=2438419}}</ref> faster disease progression in [[multiple sclerosis]],<ref>{{cite journal | vauthors = Chapman J, Vinokurov S, Achiron A, Karussis DM, Mitosek-Szewczyk K, Birnbaum M, Michaelson DM, Korczyn AD | title = APOE genotype is a major predictor of long-term progression of disability in MS | journal = Neurology | volume = 56 | issue = 3 | pages = 312–6 | date = February 2001 | pmid = 11171894 | doi = 10.1212/wnl.56.3.312 }}</ref><ref>{{cite journal | vauthors = Schmidt S, Barcellos LF, DeSombre K, Rimmler JB, Lincoln RR, Bucher P, Saunders AM, Lai E, Martin ER, Vance JM, Oksenberg JR, Hauser SL, Pericak-Vance MA, Haines JL | title = Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis | journal = American Journal of Human Genetics | volume = 70 | issue = 3 | pages = 708–17 | date = March 2002 | pmid = 11836653 | doi = 10.1086/339269 | pmc=384947}}</ref> unfavorable outcome after [[traumatic brain injury]],<ref>{{cite journal | vauthors = Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M, Tsenter J, Babaey S, Yehuda B, Groswasser Z | title = Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury | journal = Neurology | volume = 52 | issue = 2 | pages = 244–8 | date = January 1999 | pmid = 9932938 | doi = 10.1212/wnl.52.2.244 }}</ref> ischemic [[cerebrovascular disease]],<ref>{{cite journal | vauthors = McCarron MO, Delong D, Alberts MJ | title = APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis | journal = Neurology | volume = 53 | issue = 6 | pages = 1308–11 | date = October 1999 | pmid = 10522889 | doi = 10.1212/wnl.53.6.1308 }}</ref> [[sleep apnea]],<ref>{{cite journal | vauthors = Kadotani H, Kadotani T, Young T, Peppard PE, Finn L, Colrain IM, Murphy GM, Mignot E | title = Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults | journal = JAMA | volume = 285 | issue = 22 | pages = 2888–90 | date = June 2001 | pmid = 11401610 | doi = 10.1001/jama.285.22.2888 }}</ref><ref>{{cite journal | vauthors = Gottlieb DJ, DeStefano AL, Foley DJ, Mignot E, Redline S, Givelber RJ, Young T | title = APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study | journal = Neurology | volume = 63 | issue = 4 | pages = 664–8 | date = August 2004 | pmid = 15326239 | doi = 10.1212/01.wnl.0000134671.99649.32 }}</ref> accelerated [[telomere]] shortening <ref name="pmid23418430">{{cite journal | vauthors = Jacobs EG, Kroenke C, Lin J, Epel ES, Kenna HA, Blackburn EH, Rasgon NL | title = Accelerated cell aging in female APOE-ε4 carriers: implications for hormone therapy use | journal = PLOS One | volume = 8 | issue = 2 | pages = e54713 | date = February 2013 | pmid = 23418430 | pmc = 3572118 | doi = 10.1371/journal.pone.0054713 }}</ref> and reduced [[neurite]] outgrowth.<ref name="pmid18395206">{{cite journal | vauthors = Raber J | title = AR, apoE, and cognitive function | journal = Hormones and Behavior | volume = 53 | issue = 5 | pages = 706–15 | date = May 2008 | pmid = 18395206 | pmc = 2409114 | doi = 10.1016/j.yhbeh.2008.02.012 }}</ref> 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.<ref name="pmid-21659554">{{cite journal | vauthors = Huebbe P, Nebel A, Siegert S, Moehring J, Boesch-Saadatmandi C, Most E, Pallauf J, Egert S, Müller MJ, Schreiber S, Nöthlings U, Rimbach G | title = APOE ε4 is associated with higher vitamin D levels in targeted replacement mice and humans | journal = FASEB Journal | volume = 25 | issue = 9 | pages = 3262–70 | date = September 2011 | pmid = 21659554 | doi = 10.1096/fj.11-180935 }}</ref>
* {{anchor|E4}}ε4 (rs7412-C, rs429358-C) has an allele frequency of approximately 14 percent.<ref name="Meta-analysis"/> E4 has been implicated in [[atherosclerosis]],<ref name="pmid3283935">{{cite journal | vauthors = Mahley RW | title = Apolipoprotein E: cholesterol transport protein with expanding role in cell biology | journal = Science | volume = 240 | issue = 4852 | pages = 622–30 | date = April 1988 | pmid = 3283935 | doi = 10.1126/science.3283935 }}</ref> [[Alzheimer's disease]],<ref name="pmid8346443">{{cite journal | vauthors = Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA | title = Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families | journal = Science | volume = 261 | issue = 5123 | pages = 921–23 | date = August 1993 | pmid = 8346443 | doi = 10.1126/science.8346443 }}</ref><ref name="pmid8446617">{{cite journal | vauthors = Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD | title = Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 5 | pages = 1977–81 | date = March 1993 | pmid = 8446617 | pmc = 46003 | doi = 10.1073/pnas.90.5.1977 }}</ref> impaired [[cognitive function]],<ref>{{cite journal | vauthors = Deary IJ, Whiteman MC, Pattie A, Starr JM, Hayward C, Wright AF, Carothers A, Whalley LJ | title = Cognitive change and the APOE epsilon 4 allele | journal = Nature | volume = 418 | issue = 6901 | pages = 932 | date = August 2002 | pmid = 12198535 | doi = 10.1038/418932a }}</ref><ref name="Cognitive Impairment">{{cite journal | vauthors = Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC | title = Impact of APOE in mild cognitive impairment | journal = Neurology | volume = 63 | issue = 10 | pages = 1898–901 | date = November 2004 | pmid = 15557508 | doi = 10.1212/01.wnl.0000144279.21502.b7 }}</ref> reduced [[hippocampal]] volume,<ref name="Cognitive Impairment"/> [[HIV]],<ref>{{cite journal | vauthors = Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, Cavrois M, Huang Y, Mahley RW, Dolan MJ, McCune JM, Ahuja SK | title = Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 25 | pages = 8718–23 | date = June 2008 | pmid = 18562290 | doi = 10.1073/pnas.0803526105 | pmc=2438419}}</ref> faster disease progression in [[multiple sclerosis]],<ref>{{cite journal | vauthors = Chapman J, Vinokurov S, Achiron A, Karussis DM, Mitosek-Szewczyk K, Birnbaum M, Michaelson DM, Korczyn AD | title = APOE genotype is a major predictor of long-term progression of disability in MS | journal = Neurology | volume = 56 | issue = 3 | pages = 312–16 | date = February 2001 | pmid = 11171894 | doi = 10.1212/wnl.56.3.312 }}</ref><ref>{{cite journal | vauthors = Schmidt S, Barcellos LF, DeSombre K, Rimmler JB, Lincoln RR, Bucher P, Saunders AM, Lai E, Martin ER, Vance JM, Oksenberg JR, Hauser SL, Pericak-Vance MA, Haines JL | title = Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis | journal = American Journal of Human Genetics | volume = 70 | issue = 3 | pages = 708–17 | date = March 2002 | pmid = 11836653 | doi = 10.1086/339269 | pmc=384947}}</ref> unfavorable outcome after [[traumatic brain injury]],<ref>{{cite journal | vauthors = Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M, Tsenter J, Babaey S, Yehuda B, Groswasser Z | title = Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury | journal = Neurology | volume = 52 | issue = 2 | pages = 244–48 | date = January 1999 | pmid = 9932938 | doi = 10.1212/wnl.52.2.244 }}</ref> ischemic [[cerebrovascular disease]],<ref>{{cite journal | vauthors = McCarron MO, Delong D, Alberts MJ | title = APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis | journal = Neurology | volume = 53 | issue = 6 | pages = 1308–11 | date = October 1999 | pmid = 10522889 | doi = 10.1212/wnl.53.6.1308 }}</ref> [[sleep apnea]],<ref>{{cite journal | vauthors = Kadotani H, Kadotani T, Young T, Peppard PE, Finn L, Colrain IM, Murphy GM, Mignot E | title = Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults | journal = JAMA | volume = 285 | issue = 22 | pages = 2888–90 | date = June 2001 | pmid = 11401610 | doi = 10.1001/jama.285.22.2888 }}</ref><ref>{{cite journal | vauthors = Gottlieb DJ, DeStefano AL, Foley DJ, Mignot E, Redline S, Givelber RJ, Young T | title = APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study | journal = Neurology | volume = 63 | issue = 4 | pages = 664–68 | date = August 2004 | pmid = 15326239 | doi = 10.1212/01.wnl.0000134671.99649.32 }}</ref> accelerated [[telomere]] shortening <ref name="pmid23418430">{{cite journal | vauthors = Jacobs EG, Kroenke C, Lin J, Epel ES, Kenna HA, Blackburn EH, Rasgon NL | title = Accelerated cell aging in female APOE-ε4 carriers: implications for hormone therapy use | journal = PLOS One | volume = 8 | issue = 2 | pages = e54713 | date = February 2013 | pmid = 23418430 | pmc = 3572118 | doi = 10.1371/journal.pone.0054713 }}</ref> and reduced [[neurite]] outgrowth.<ref name="pmid18395206">{{cite journal | vauthors = Raber J | title = AR, apoE, and cognitive function | journal = Hormones and Behavior | volume = 53 | issue = 5 | pages = 706–15 | date = May 2008 | pmid = 18395206 | pmc = 2409114 | doi = 10.1016/j.yhbeh.2008.02.012 }}</ref> 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.<ref name="pmid-21659554">{{cite journal | vauthors = Huebbe P, Nebel A, Siegert S, Moehring J, Boesch-Saadatmandi C, Most E, Pallauf J, Egert S, Müller MJ, Schreiber S, Nöthlings U, Rimbach G | title = APOE ε4 is associated with higher vitamin D levels in targeted replacement mice and humans | journal = FASEB Journal | volume = 25 | issue = 9 | pages = 3262–70 | date = September 2011 | pmid = 21659554 | doi = 10.1096/fj.11-180935 }}</ref>


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.<ref>{{cite journal | vauthors = Mondadori CR, de Quervain DJ, Buchmann A, Mustovic H, Wollmer MA, Schmidt CF, Boesiger P, Hock C, Nitsch RM, Papassotiropoulos A, Henke K | title = Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers | journal = Cerebral Cortex | volume = 17 | issue = 8 | pages = 1934–47 | date = August 2007 | pmid = 17077159 | doi = 10.1093/cercor/bhl103 }}</ref>
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.<ref>{{cite journal | vauthors = Mondadori CR, de Quervain DJ, Buchmann A, Mustovic H, Wollmer MA, Schmidt CF, Boesiger P, Hock C, Nitsch RM, Papassotiropoulos A, Henke K | title = Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers | journal = Cerebral Cortex | volume = 17 | issue = 8 | pages = 1934–47 | date = August 2007 | pmid = 17077159 | doi = 10.1093/cercor/bhl103 }}</ref>


== Function ==
== Function ==
APOE transports [[lipoprotein]]s, 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]], [[kidney]]s, and [[spleen]].<ref name="cardiogenetics">{{cite book | last1 = Baars | first1 = H.F. | last2 = van der Smagt | first2 = J.J. | last3 = Doevandans | first3 = P.A.F.M. | title = Clinical Cardiogenetics | date = 2011 | publisher = Springer | location = London | isbn = 9781849964715 | name-list-format = vanc }}</ref> In the nervous system, non-neuronal cell types, most notably [[Astrocyte|astroglia]] and [[microglia]], are the primary producers of APOE, while neurons preferentially express the receptors for APOE.<ref>{{cite journal | vauthors = Zhang Z, Mu J, Li J, Li W, Song J | title = Aberrant apolipoprotein E expression and cognitive dysfunction in patients with poststroke depression | journal = Genetic Testing and Molecular Biomarkers | volume = 17 | issue = 1 | pages = 47–51 | date = January 2013 | pmid = 23171142 | doi = 10.1089/gtmb.2012.0253 | pmc=3525887}}</ref> There are seven currently identified mammalian [[Receptor (biochemistry)|receptor]]s for APOE which belong to the evolutionarily conserved LDLR family.<ref>{{cite journal | vauthors = Rogers JT, Weeber EJ | title = Reelin and apoE actions on signal transduction, synaptic function and memory formation | journal = Neuron Glia Biology | volume = 4 | issue = 3 | pages = 259–70 | date = August 2008 | pmid = 19674510 | doi = 10.1017/S1740925X09990184 }}</ref>
APOE transports [[lipid]]s, 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]], [[kidney]]s, and [[spleen]].<ref name="cardiogenetics">{{cite book | last1 = Baars | first1 = HF | last2 = van der Smagt | first2 = JJ | last3 = Doevandans | first3 = PAFM | title = Clinical Cardiogenetics | date = 2011 | publisher = Springer | location = London | isbn = 978-1849964715 | name-list-format = vanc }}</ref> In the nervous system, non-neuronal cell types, most notably [[Astrocyte|astroglia]] and [[microglia]], are the primary producers of APOE, while neurons preferentially express the receptors for APOE.<ref>{{cite journal | vauthors = Zhang Z, Mu J, Li J, Li W, Song J | title = Aberrant apolipoprotein E expression and cognitive dysfunction in patients with poststroke depression | journal = Genetic Testing and Molecular Biomarkers | volume = 17 | issue = 1 | pages = 47–51 | date = January 2013 | pmid = 23171142 | pmc = 3525887 | doi = 10.1089/gtmb.2012.0253 }}</ref> There are seven currently identified mammalian [[Receptor (biochemistry)|receptor]]s for APOE which belong to the evolutionarily conserved LDLR family.<ref>{{cite journal | vauthors = Rogers JT, Weeber EJ | title = Reelin and apoE actions on signal transduction, synaptic function and memory formation | journal = Neuron Glia Biology | volume = 4 | issue = 3 | pages = 259–70 | date = August 2008 | pmid = 19674510 | doi = 10.1017/S1740925X09990184 }}</ref>


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.<ref name="entrez"/> More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including [[Alzheimer's disease]]  (AD), [[Immune system|immunoregulation]], and [[cognition]].<ref name="encyclopedia"/> Though 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.<ref>{{vcite2 journal | vauthors = Jiang L, Zhong J, Dou X, Cheng C, Huang Z, Sun X | title = Effects of ApoE on intracellular calcium levels and apoptosis of neurons after mechanical injury | journal = Neuroscience | volume = 301 | pages = 375–83 | date = Aug 2015 | pmid = 26073697 | doi = 10.1016/j.neuroscience.2015.06.005 }}</ref>
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.<ref name="entrez"/> More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including [[Alzheimer's disease]]  (AD), [[Immune system|immunoregulation]], and [[cognition]].<ref name="encyclopedia"/> Though 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.<ref>{{vcite2 journal | vauthors = Jiang L, Zhong J, Dou X, Cheng C, Huang Z, Sun X | title = Effects of ApoE on intracellular calcium levels and apoptosis of neurons after mechanical injury | journal = Neuroscience | volume = 301 | pages = 375–83 | date = Aug 2015 | pmid = 26073697 | doi = 10.1016/j.neuroscience.2015.06.005 }}</ref>
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===Alzheimer's disease===
===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.<ref>{{cite journal | vauthors = Sadigh-Eteghad S, Talebi M, Farhoudi M | title = Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer`s disease. A meta-analysis | journal = Neurosciences | volume = 17 | issue = 4 | pages = 321–6 | date = October 2012 | pmid = 23022896 }}</ref> However, the E4 variant does not correlate with risk in every population. Nigerian blacks have the highest observed frequency of the APO E*4 allele in world populations,<ref name=":0">{{cite journal | vauthors = Sepehrnia B, Kamboh MI, Adams-Campbell LL, Bunker CH, Nwankwo M, Majumder PP, Ferrell RE | title = Genetic studies of human apolipoproteins. X. The effect of the apolipoprotein E polymorphism on quantitative levels of lipoproteins in Nigerian blacks | journal = American Journal of Human Genetics | volume = 45 | issue = 4 | pages = 586–91 | date = October 1989 | pmid = 2491016 | pmc = 1683508 }}</ref> but AD is rare among them.<ref name=":0" /><ref name=":1">{{cite journal | vauthors = Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen P, Tuomilehto J, Nissinen A | title = Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease | journal = Neuroepidemiology | volume = 17 | issue = 1 | pages = 14–20 | date = 1998-01-01 | pmid = 9549720 | doi=10.1159/000026149}}</ref> This may be due to their low cholesterol levels.<ref name=":0" /><ref name=":1" /><ref>{{cite journal | vauthors = Petanceska SS, DeRosa S, Sharma A, Diaz N, Duff K, Tint SG, Refolo LM, Pappolla M | title = Changes in apolipoprotein E expression in response to dietary and pharmacological modulation of cholesterol | journal = Journal of Molecular Neuroscience | volume = 20 | issue = 3 | pages = 395–406 | date = 2003-01-01 | pmid = 14501024 | doi = 10.1385/JMN:20:3:395 }}</ref><ref name=":2">{{cite journal | vauthors = Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Iivonen S, Mannermaa A, Tuomilehto J, Nissinen A, Soininen H | title = Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease | journal = Annals of Internal Medicine | volume = 137 | issue = 3 | pages = 149–55 | date = August 2002 | pmid = 12160362 | doi=10.7326/0003-4819-137-3-200208060-00006}}</ref> 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. This may be caused by an interaction with [[amyloid]].<ref name="pmid1625800">{{cite journal | vauthors = Wisniewski T, Frangione B | title = Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid | journal = Neuroscience Letters | volume = 135 | issue = 2 | pages = 235–8 | date = February 1992 | pmid = 1625800 | doi = 10.1016/0304-3940(92)90444-C }}</ref> 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.<ref name="Neuron">{{cite journal | vauthors = Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE | title = ApoE promotes the proteolytic degradation of Abeta | journal = Neuron | volume = 58 | issue = 5 | pages = 681–93 | date = June 2008 | pmid = 18549781 | pmc = 2493297 | doi = 10.1016/j.neuron.2008.04.010 | publisher = Cell Press | laydate = 2008-06-13 | laysource = ScienceDaily | laysummary = http://www.sciencedaily.com/releases/2008/06/080611135123.htm }}</ref>
The E4 variant is the largest known genetic risk factor for late-onset sporadic [[Alzheimer's disease]] (AD) in a variety of ethnic groups.<ref>{{cite journal | vauthors = Sadigh-Eteghad S, Talebi M, Farhoudi M | title = Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer`s disease. A meta-analysis | journal = Neurosciences | volume = 17 | issue = 4 | pages = 321–26 | date = October 2012 | pmid = 23022896 }}</ref> However, the E4 variant does not correlate with risk in every population. Nigerian blacks have the highest observed frequency of the APO E*4 allele in world populations,<ref name=":0">{{cite journal | vauthors = Sepehrnia B, Kamboh MI, Adams-Campbell LL, Bunker CH, Nwankwo M, Majumder PP, Ferrell RE | title = Genetic studies of human apolipoproteins. X. The effect of the apolipoprotein E polymorphism on quantitative levels of lipoproteins in Nigerian blacks | journal = American Journal of Human Genetics | volume = 45 | issue = 4 | pages = 586–91 | date = October 1989 | pmid = 2491016 | pmc = 1683508 }}</ref> but AD is rare among them.<ref name=":0" /><ref name=":1">{{cite journal | vauthors = Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen P, Tuomilehto J, Nissinen A | title = Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease | journal = Neuroepidemiology | volume = 17 | issue = 1 | pages = 14–20 | date = 1998-01-01 | pmid = 9549720 | doi=10.1159/000026149}}</ref> This may be due to their low cholesterol levels.<ref name=":0" /><ref name=":1" /><ref>{{cite journal | vauthors = Petanceska SS, DeRosa S, Sharma A, Diaz N, Duff K, Tint SG, Refolo LM, Pappolla M | title = Changes in apolipoprotein E expression in response to dietary and pharmacological modulation of cholesterol | journal = Journal of Molecular Neuroscience | volume = 20 | issue = 3 | pages = 395–406 | date = 2003-01-01 | pmid = 14501024 | doi = 10.1385/JMN:20:3:395 }}</ref><ref name=":2">{{cite journal | vauthors = Kivipelto M, Helkala EL, Laakso MP, Hänninen T, Hallikainen M, Alhainen K, Iivonen S, Mannermaa A, Tuomilehto J, Nissinen A, Soininen H | title = Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease | journal = Annals of Internal Medicine | volume = 137 | issue = 3 | pages = 149–55 | date = August 2002 | pmid = 12160362 | doi=10.7326/0003-4819-137-3-200208060-00006}}</ref> 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. This may be caused by an interaction with [[amyloid]].<ref name="pmid1625800">{{cite journal | vauthors = Wisniewski T, Frangione B | title = Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid | journal = Neuroscience Letters | volume = 135 | issue = 2 | pages = 235–38 | date = February 1992 | pmid = 1625800 | doi = 10.1016/0304-3940(92)90444-C }}</ref> 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.<ref name="Neuron">{{cite journal | vauthors = Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE | title = ApoE promotes the proteolytic degradation of Abeta | journal = Neuron | volume = 58 | issue = 5 | pages = 681–93 | date = June 2008 | pmid = 18549781 | pmc = 2493297 | doi = 10.1016/j.neuron.2008.04.010 | publisher = Cell Press | laydate = 2008-06-13 | laysource = ScienceDaily | laysummary = https://www.sciencedaily.com/releases/2008/06/080611135123.htm }}</ref>


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.<ref name="HauserRyan2013">{{cite journal | vauthors = Hauser PS, Ryan RO | title = Impact of apolipoprotein E on Alzheimer's disease | journal = Current Alzheimer Research | volume = 10 | issue = 8 | pages = 809–17 | date = October 2013 | pmid = 23919769 | pmc = 3995977 | doi = 10.2174/15672050113109990156 }}</ref> There is also evidence that the ApoE2 allele may serve a protective role in AD.<ref name="pmid7920638">{{cite journal | vauthors = Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE | title = Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease | journal = Nature Genetics | volume = 7 | issue = 2 | pages = 180–4 | date = June 1994 | pmid = 7920638 | doi = 10.1038/ng0694-180 }}</ref> 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.<ref name="ReferenceA">{{cite journal | vauthors = Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM | title = 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 | journal = JAMA | volume = 278 | issue = 16 | pages = 1349–56 | year = 1997 | pmid = 9343467 | doi = 10.1001/jama.1997.03550160069041 }}</ref>
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.<ref name="HauserRyan2013">{{cite journal | vauthors = Hauser PS, Ryan RO | title = Impact of apolipoprotein E on Alzheimer's disease | journal = Current Alzheimer Research | volume = 10 | issue = 8 | pages = 809–17 | date = October 2013 | pmid = 23919769 | pmc = 3995977 | doi = 10.2174/15672050113109990156 }}</ref> There is also evidence that the ApoE2 allele may serve a protective role in AD.<ref name="pmid7920638">{{cite journal | vauthors = Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC, Rimmler JB, Locke PA, Conneally PM, Schmader KE | title = Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease | journal = Nature Genetics | volume = 7 | issue = 2 | pages = 180–84 | date = June 1994 | pmid = 7920638 | doi = 10.1038/ng0694-180 }}</ref> 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.<ref name="ReferenceA">{{cite journal | vauthors = Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM | title = 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 | journal = JAMA | volume = 278 | issue = 16 | pages = 1349–56 | year = 1997 | pmid = 9343467 | doi = 10.1001/jama.1997.03550160069041 }}</ref>


{| class="wikitable"
{| class="wikitable"
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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 the risk that the individual will later develop AD.<ref name=":2" /> 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.<ref name=":2" />
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 the risk that the individual will later develop AD.<ref name=":2" /> 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.<ref name=":2" />


Women are more likely to develop AD than men across most ages and APOE genotypes. Premorbid women with the ε4 allele have significantly more neurological dysfunction than men.<ref>{{Cite journal|last=Damoiseaux|first=Jessica S.|last2=Seeley|first2=William W.|last3=Zhou|first3=Juan|last4=Shirer|first4=William R.|last5=Coppola|first5=Giovanni|last6=Karydas|first6=Anna|last7=Rosen|first7=Howard J.|last8=Miller|first8=Bruce L.|last9=Kramer|first9=Joel H.|date=2012-06-13|title=Gender Modulates the APOE ε4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels|url=http://www.jneurosci.org/content/32/24/8254|journal=Journal of Neuroscience|language=en|volume=32|issue=24|pages=8254–8262|doi=10.1523/JNEUROSCI.0305-12.2012|issn=0270-6474|pmid=22699906}}</ref>
Women are more likely to develop AD than men across most ages and APOE genotypes. Premorbid women with the ε4 allele have significantly more neurological dysfunction than men.<ref>{{Cite journal|last=Damoiseaux|first=Jessica S.|last2=Seeley|first2=William W.|last3=Zhou|first3=Juan|last4=Shirer|first4=William R.|last5=Coppola|first5=Giovanni|last6=Karydas|first6=Anna|last7=Rosen|first7=Howard J.|last8=Miller|first8=Bruce L.|last9=Kramer|first9=Joel H.|date=2012-06-13|title=Gender Modulates the APOE ε4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels|url=http://www.jneurosci.org/content/32/24/8254|journal=Journal of Neuroscience|language=en|volume=32|issue=24|pages=8254–62|doi=10.1523/JNEUROSCI.0305-12.2012|issn=0270-6474|pmid=22699906|pmc=3394933}}</ref>


===Atherosclerosis===
===Atherosclerosis===
[[Knockout mouse|Knockout mice]] that lack the apolipoprotein-E gene (ApoE<sup>−/−</sup>) develop extreme [[hypercholesterolemia]] when fed a high-fat diet.<ref name="pmid20210786">{{cite journal | vauthors = McNeill E, Channon KM, Greaves DR | title = Inflammatory cell recruitment in cardiovascular disease: murine models and potential clinical applications | journal = Clinical Science | volume = 118 | issue = 11 | pages = 641–55 | date = June 2010 | pmid = 20210786 | doi = 10.1042/CS20090488 }}</ref>
[[Knockout mouse|Knockout mice]] that lack the apolipoprotein-E gene (ApoE<sup>−/−</sup>) develop extreme [[hypercholesterolemia]] when fed a high-fat diet.<ref name="pmid20210786">{{cite journal | vauthors = McNeill E, Channon KM, Greaves DR | title = Inflammatory cell recruitment in cardiovascular disease: murine models and potential clinical applications | journal = Clinical Science | volume = 118 | issue = 11 | pages = 641–55 | date = June 2010 | pmid = 20210786 | doi = 10.1042/CS20090488 }}</ref>
===Malaria===
ApoE<sup>−/−</sup> 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]].<ref name="pmid27647324">{{cite journal | vauthors = Kassa FA, Van Den Ham K, Rainone A, Fournier S, Boilard E, Olivier M | title = Absence of apolipoprotein E protects mice from cerebral malaria | journal = Scientific Reports | volume = 6 | issue =  | pages = 33615 | date = September 2016 | pmid = 27647324 | pmc = 5028887 | doi = 10.1038/srep33615 }}</ref> Human studies have shown that the ApoE2 polymorphism correlates with earlier infection and ApoE3/4 polymorphisms increase likelihood of severe malaria.<ref name="pmid14985370">{{cite journal | vauthors = Wozniak MA, Riley EM, Itzhaki RF | title = Apolipoprotein E polymorphisms and risk of malaria | journal = Journal of Medical Genetics | volume = 41 | issue = 3 | pages = 145–46 | date = March 2004 | pmid = 14985370 | pmc = 1735716 | doi =  10.1136/jmg.2003.014613 }}</ref>


== Interactions ==
== Interactions ==
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==Evolution==
==Evolution==


Apolipoproteins are not unique to mammals, many vertebrates, both terrestrial and marine, have versions of them.<ref name="Babin_1997">{{cite journal | vauthors = Babin PJ, Thisse C, Durliat M, Andre M, Akimenko MA, Thisse B | title = Both apolipoprotein E and A-I genes are present in a nonmammalian vertebrate and are highly expressed during embryonic development | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 16 | pages = 8622–7 | year = 1997 | pmid = 9238027 | pmc = 23048 | doi = }}</ref>  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.  It is believed that  the APOE arose via gene duplications of APOC-I before the fish-mammal split 400 million years ago.<ref name="Huebbe_2017">{{cite journal | vauthors = Huebbe P, Rimbach G | title = Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors | journal = Ageing Research Reviews | volume = 37 | issue = | pages = 146–161 | year = 2017 | pmid = 28647612 | doi = 10.1016/j.arr.2017.06.002 }}</ref>
Apolipoproteins are not unique to mammals. Many terrestrial and marine vertebrates have versions of them.<ref name="Babin_1997">{{cite journal | vauthors = Babin PJ, Thisse C, Durliat M, Andre M, Akimenko MA, Thisse B | title = Both apolipoprotein E and A-I genes are present in a nonmammalian vertebrate and are highly expressed during embryonic development | journal = PNAS | volume = 94 | issue = 16 | pages = 8622–27 | year = 1997 | pmid = 9238027 | pmc = 23048 | doi = 10.1073/pnas.94.16.8622}}</ref>  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.  It is believed that  the APOE arose via gene duplications of APOC-I before the fish-mammal split 400 million years ago.<ref name="Huebbe_2017">{{cite journal | vauthors = Huebbe P, Rimbach G | title = Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors | journal = Ageing Research Reviews | volume = 37 | issue = | pages = 146–61 | year = 2017 | pmid = 28647612 | doi = 10.1016/j.arr.2017.06.002 }}</ref>


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 was E4.  After the primate-human split there were four amino acid changes in the human lineage, three of those changes had no effect (V147L, A18T, A135V), but the fourth substitution 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 the exact same substitutions were found in Denisovan APOE.<ref name="McIntosh_2012">{{cite journal | vauthors = McIntosh AM, Bennett C, Dickson D, Anestis SF, Watts DP, Webster TH, Fontenot MB, Bradley BJ | title = The apolipoprotein E (APOE) gene appears functionally monomorphic in chimpanzees (Pan troglodytes) | journal = PLOS One | volume = 7 | issue = 10 | pages = e47760 | year = 2012 | pmid = 23112842 | pmc = 3480407 | doi = 10.1371/journal.pone.0047760 }}</ref>
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 was E4.  After the primate-human split there were four amino acid changes in the human lineage, three of those changes had no effect (V174L, A18T, A135V), but the fourth substitution 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 the exact same substitutions were found in Denisovan APOE.<ref name="McIntosh_2012">{{cite journal | vauthors = McIntosh AM, Bennett C, Dickson D, Anestis SF, Watts DP, Webster TH, Fontenot MB, Bradley BJ | title = The apolipoprotein E (APOE) gene appears functionally monomorphic in chimpanzees (Pan troglodytes) | journal = PLOS One | volume = 7 | issue = 10 | pages = e47760 | year = 2012 | pmid = 23112842 | pmc = 3480407 | doi = 10.1371/journal.pone.0047760 }}</ref>


About 220,000 years ago, an arginine to cytosine substitution took place at amino acid 112 of the APOE4 gene and this resulted in the E3 allele.  Finally, 80,000 years ago another arginine to cytosine substitution at amino acid 158 of the APOE3 gene created the E2 allele.<ref name="pmid15101252">{{cite journal | vauthors = Finch CE, Stanford CB | title = Meat-adaptive genes and the evolution of slower aging in humans | journal = The Quarterly Review of Biology | volume = 79 | issue = 1 | pages = 3–50 | year = 2004 | pmid = 15101252 | doi = 10.1086/381662 }}</ref><ref name="Huebbe_2017" />
About 220,000 years ago, an arginine to cysteine substitution took place at amino acid 112 (Arg112Cys) 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.<ref name="pmid15101252">{{cite journal | vauthors = Finch CE, Stanford CB | title = Meat-adaptive genes and the evolution of slower aging in humans | journal = The Quarterly Review of Biology | volume = 79 | issue = 1 | pages = 3–50 | year = 2004 | pmid = 15101252 | doi = 10.1086/381662 }}</ref><ref name="Huebbe_2017" />


== References ==
== References ==
{{Reflist|33em}}
{{Reflist}}


== Further reading ==
== Further reading ==
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* {{cite journal | vauthors = Gunzburg MJ, Perugini MA, Howlett GJ | title = Structural basis for the recognition and cross-linking of amyloid fibrils by human apolipoprotein E | journal = The Journal of Biological Chemistry | volume = 282 | issue = 49 | pages = 35831–41 | date = December 2007 | pmid = 17916554 | doi = 10.1074/jbc.M706425200 }}
* {{cite journal | vauthors = Gunzburg MJ, Perugini MA, Howlett GJ | title = Structural basis for the recognition and cross-linking of amyloid fibrils by human apolipoprotein E | journal = The Journal of Biological Chemistry | volume = 282 | issue = 49 | pages = 35831–41 | date = December 2007 | pmid = 17916554 | doi = 10.1074/jbc.M706425200 }}
* {{cite journal | vauthors = Kolovou GD, Anagnostopoulou KK | title = Apolipoprotein E polymorphism, age and coronary heart disease | journal = Ageing Research Reviews | volume = 6 | issue = 2 | pages = 94–108 | date = August 2007 | pmid = 17224309 | doi = 10.1016/j.arr.2006.11.001 }}
* {{cite journal | vauthors = Kolovou GD, Anagnostopoulou KK | title = Apolipoprotein E polymorphism, age and coronary heart disease | journal = Ageing Research Reviews | volume = 6 | issue = 2 | pages = 94–108 | date = August 2007 | pmid = 17224309 | doi = 10.1016/j.arr.2006.11.001 }}
* {{cite journal | vauthors = Lambert JC, Amouyel P | title = Genetic heterogeneity of Alzheimer's disease: complexity and advances | journal = Psychoneuroendocrinology | volume = 32 Suppl 1 | issue =  | pages = S62-70 | date = August 2007 | pmid = 17659844 | doi = 10.1016/j.psyneuen.2007.05.015 }}
* {{cite journal | vauthors = Lambert JC, Amouyel P | title = Genetic heterogeneity of Alzheimer's disease: complexity and advances |journal =[[Psychoneuroendocrinology (journal)|Psychoneuroendocrinology]] | volume = 32 Suppl 1 | issue =  | pages = S62–70 | date = August 2007 | pmid = 17659844 | doi = 10.1016/j.psyneuen.2007.05.015 }}
* {{cite journal | vauthors = Raber J | title = Role of apolipoprotein E in anxiety | journal = Neural Plasticity | volume = 2007 | issue =  | pages = 91236 | year = 2007 | pmid = 17710250 | pmc = 1940061 | doi = 10.1155/2007/91236 }}
* {{cite journal | vauthors = Raber J | title = Role of apolipoprotein E in anxiety | journal = Neural Plasticity | volume = 2007 | issue =  | pages = 91236 | year = 2007 | pmid = 17710250 | pmc = 1940061 | doi = 10.1155/2007/91236 }}
* {{cite journal | vauthors = Ye J | title = Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus | journal = PLoS Pathogens | volume = 3 | issue = 8 | pages = e108 | date = August 2007 | pmid = 17784784 | pmc = 1959368 | doi = 10.1371/journal.ppat.0030108 }}
* {{cite journal | vauthors = Ye J | title = Reliance of host cholesterol metabolic pathways for the life cycle of hepatitis C virus | journal = PLoS Pathogens | volume = 3 | issue = 8 | pages = e108 | date = August 2007 | pmid = 17784784 | pmc = 1959368 | doi = 10.1371/journal.ppat.0030108 }}
* {{cite journal | vauthors = Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, Keavney B, Collins R, Wiman B, de Faire U, Danesh J | title = Association of apolipoprotein E genotypes with lipid levels and coronary risk | journal = JAMA | volume = 298 | issue = 11 | pages = 1300–11 | date = September 2007 | pmid = 17878422 | doi = 10.1001/jama.298.11.1300 }}
* {{cite journal | vauthors = Bennet AM, Di Angelantonio E, Ye Z, Wensley F, Dahlin A, Ahlbom A, Keavney B, Collins R, Wiman B, de Faire U, Danesh J | title = Association of apolipoprotein E genotypes with lipid levels and coronary risk | journal = JAMA | volume = 298 | issue = 11 | pages = 1300–11 | date = September 2007 | pmid = 17878422 | doi = 10.1001/jama.298.11.1300 }}
* {{cite journal | vauthors = Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA | title = The role of viruses and of APOE in dementia | journal = Annals of the New York Academy of Sciences | volume = 1019 | issue = 1 | pages = 15–8 | date = June 2004 | pmid = 15246985 | doi = 10.1196/annals.1297.003 }}
* {{cite journal | vauthors = Itzhaki RF, Dobson CB, Shipley SJ, Wozniak MA | title = The role of viruses and of APOE in dementia | journal = Annals of the New York Academy of Sciences | volume = 1019 | issue = 1 | pages = 15–18 | date = June 2004 | pmid = 15246985 | doi = 10.1196/annals.1297.003 }}
* {{cite journal | vauthors = Ashford JW | title = APOE genotype effects on Alzheimer's disease onset and epidemiology | journal = Journal of Molecular Neuroscience | volume = 23 | issue = 3 | pages = 157–65 | year = 2004 | pmid = 15181244 | doi = 10.1385/JMN:23:3:157 }}
* {{cite journal | vauthors = Ashford JW | title = APOE genotype effects on Alzheimer's disease onset and epidemiology | journal = Journal of Molecular Neuroscience | volume = 23 | issue = 3 | pages = 157–65 | year = 2004 | pmid = 15181244 | doi = 10.1385/JMN:23:3:157 }}
* {{cite journal | vauthors = Huang Y, Weisgraber KH, Mucke L, Mahley RW | title = Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease | journal = Journal of Molecular Neuroscience | volume = 23 | issue = 3 | pages = 189–204 | year = 2004 | pmid = 15181247 | doi = 10.1385/JMN:23:3:189 }}
* {{cite journal | vauthors = Huang Y, Weisgraber KH, Mucke L, Mahley RW | title = Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease | journal = Journal of Molecular Neuroscience | volume = 23 | issue = 3 | pages = 189–204 | year = 2004 | pmid = 15181247 | doi = 10.1385/JMN:23:3:189 }}
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* {{cite journal | vauthors = Beffert U, Danik M, Krzywkowski P, Ramassamy C, Berrada F, Poirier J | title = The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease | journal = Brain Research. Brain Research Reviews | volume = 27 | issue = 2 | pages = 119–42 | date = July 1998 | pmid = 9622609 | doi = 10.1016/S0165-0173(98)00008-3 }}
* {{cite journal | vauthors = Beffert U, Danik M, Krzywkowski P, Ramassamy C, Berrada F, Poirier J | title = The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease | journal = Brain Research. Brain Research Reviews | volume = 27 | issue = 2 | pages = 119–42 | date = July 1998 | pmid = 9622609 | doi = 10.1016/S0165-0173(98)00008-3 }}
* {{cite journal | vauthors = Roses AD, Einstein G, Gilbert J, Goedert M, Han SH, Huang D, Hulette C, Masliah E, Pericak-Vance MA, Saunders AM, Schmechel DE, Strittmatter WJ, Weisgraber KH, Xi PT | title = Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism | journal = Annals of the New York Academy of Sciences | volume = 777 | issue = 1 | pages = 146–57 | date = January 1996 | pmid = 8624078 | doi = 10.1111/j.1749-6632.1996.tb34413.x }}
* {{cite journal | vauthors = Roses AD, Einstein G, Gilbert J, Goedert M, Han SH, Huang D, Hulette C, Masliah E, Pericak-Vance MA, Saunders AM, Schmechel DE, Strittmatter WJ, Weisgraber KH, Xi PT | title = Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism | journal = Annals of the New York Academy of Sciences | volume = 777 | issue = 1 | pages = 146–57 | date = January 1996 | pmid = 8624078 | doi = 10.1111/j.1749-6632.1996.tb34413.x }}
* {{cite journal | vauthors = Strittmatter WJ, Roses AD | title = Apolipoprotein E and Alzheimer disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 11 | pages = 4725–7 | date = May 1995 | pmid = 7761390 | pmc = 41779 | doi = 10.1073/pnas.92.11.4725 }}
* {{cite journal | vauthors = Strittmatter WJ, Roses AD | title = Apolipoprotein E and Alzheimer disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 11 | pages = 4725–27 | date = May 1995 | pmid = 7761390 | pmc = 41779 | doi = 10.1073/pnas.92.11.4725 }}
* {{cite journal | vauthors = de Knijff P, van den Maagdenberg AM, Frants RR, Havekes LM | title = Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels | journal = Human Mutation | volume = 4 | issue = 3 | pages = 178–94 | year = 1995 | pmid = 7833947 | doi = 10.1002/humu.1380040303 }}
* {{cite journal | vauthors = de Knijff P, van den Maagdenberg AM, Frants RR, Havekes LM | title = Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels | journal = Human Mutation | volume = 4 | issue = 3 | pages = 178–94 | year = 1995 | pmid = 7833947 | doi = 10.1002/humu.1380040303 }}
* {{cite journal | vauthors = Moriyama K, Sasaki J, Matsunaga A, Arakawa F, Takada Y, Araki K, Kaneko S, Arakawa K | title = Apolipoprotein E1 Lys-146----Glu with type III hyperlipoproteinemia | journal = Biochimica et Biophysica Acta | volume = 1128 | issue = 1 | pages = 58–64 | date = September 1992 | pmid = 1356443 | doi = 10.1016/0005-2760(92)90257-V }}
* {{cite journal | vauthors = Moriyama K, Sasaki J, Matsunaga A, Arakawa F, Takada Y, Araki K, Kaneko S, Arakawa K | title = Apolipoprotein E1 Lys-146----Glu with type III hyperlipoproteinemia | journal = Biochimica et Biophysica Acta | volume = 1128 | issue = 1 | pages = 58–64 | date = September 1992 | pmid = 1356443 | doi = 10.1016/0005-2760(92)90257-V }}
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== External links ==
== External links ==
* {{MeshName|Apolipoproteins+E}}
* {{MeshName|Apolipoproteins+E}}
* [http://apoe4.info apoe4.info - website for APOE-epsilon-4 carriers]
* [http://apoe4.info apoe4.info – website for APOE-epsilon-4 carriers]
* {{UCSC gene info|APOE}}
* {{UCSC gene info|APOE}}


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View/Edit Human

Apolipoprotein E (ApoE) is a class of proteins involved in the metabolism of fats in the body. It is important in Alzheimer's disease and cardiovascular disease.[1]

Lipoproteins are molecules composed of fats and proteins. Apolipoprotein E is a fat-binding protein (apolipoprotein) that is part of the chylomicron and intermediate-density lipoprotein (IDLs). These are essential for the normal processing (catabolism) of triglyceride-rich lipoproteins.[2] In peripheral tissues, ApoE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism. 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.[3] ApoE is the principal cholesterol carrier in the brain.[4]

Structure

Gene

The gene, APOE, is mapped to chromosome 19 in a cluster with apolipoprotein C1 (APOC-I) 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.[5] In melanocytic cells APOE gene expression may be regulated by MITF.[6]

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.[7]

Polymorphisms

SNP: Apolipoprotein E
GeneApoE
Chromosome19
External databases
EnsemblHuman SNPView
dbSNP429358
HapMap429358
SNPedia429358

APOE is polymorphic,[8][9] with three major alleles (epsilon 2, epsilon 3, and epsilon 4): APOE-ε2 (cys112, cys158), APOE-ε3 (cys112, arg158), and APOE-ε4 (arg112, arg158).[1][10][11] Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158,[12][13][14] these differences alter APOE structure and function. These have physiological consequences:

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.[37]

Function

APOE transports lipids, 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.[10] 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.[38] There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved LDLR family.[39]

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.[2] 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.[1] Though 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.[40]

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) [41] to natural killer T cell as well as modulation of inflammation and oxidation.[42] 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.[43]

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.[44] However, the E4 variant does not correlate with risk in every population. Nigerian blacks have the highest observed frequency of the APO E*4 allele in world populations,[45] but AD is rare among them.[45][46] This may be due to their low cholesterol levels.[45][46][47][48] 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. This may be caused by an interaction with amyloid.[49] 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.[50]

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.[51] There is also evidence that the ApoE2 allele may serve a protective role in AD.[52] 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.[53]

Estimated worldwide human allele frequencies of ApoE * in Caucasian population[53]
Allele ε2 ε3 ε4
General Frequency 8.4% 77.9% 13.7%
AD Frequency 3.9% 59.4% 36.7%

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 the risk that the individual will later develop AD.[48] 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.[48]

Women are more likely to develop AD than men across most ages and APOE genotypes. Premorbid women with the ε4 allele have significantly more neurological dysfunction than men.[54]

Atherosclerosis

Knockout mice that lack the apolipoprotein-E gene (ApoE−/−) develop extreme hypercholesterolemia when fed a high-fat diet.[55]

Malaria

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.[56] Human studies have shown that the ApoE2 polymorphism correlates with earlier infection and ApoE3/4 polymorphisms increase likelihood of severe malaria.[57]

Interactions

Interactive pathway map

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

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Statin Pathway edit
  1. ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

Evolution

Apolipoproteins are not unique to mammals. Many terrestrial and marine vertebrates have versions of them.[58] 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. It is believed that the APOE arose via gene duplications of APOC-I before the fish-mammal split 400 million years ago.[59]

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 was E4. After the primate-human split there were four amino acid changes in the human lineage, three of those changes had no effect (V174L, A18T, A135V), but the fourth substitution 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 the exact same substitutions were found in Denisovan APOE.[60]

About 220,000 years ago, an arginine to cysteine substitution took place at amino acid 112 (Arg112Cys) 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.[61][59]

References

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  2. ↑ 2.0 2.1 "Entrez Gene: APOE apolipoprotein E".
  3. ↑ Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G (February 2013). "Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy". Nature Reviews. Neurology. 9 (2): 106–18. doi:10.1038/nrneurol.2012.263. PMC 3726719. PMID 23296339.
  4. ↑ Puglielli L, Tanzi RE, Kovacs DM (April 2003). "Alzheimer's disease: the cholesterol connection". Nature Neuroscience. 6 (4): 345–51. doi:10.1038/nn0403-345. PMID 12658281.
  5. ↑ Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P (January 2001). "A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis". Molecular Cell. 7 (1): 161–71. doi:10.1016/S1097-2765(01)00164-2. PMID 11172721.
  6. ↑ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (December 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
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  12. ↑ Online Mendelian Inheritance in Man (OMIM) APOE3 isoform, hyperlipoproteinemia, type III, autosomal recessive -107741#0015
  13. ↑ Online Mendelian Inheritance in Man (OMIM) APOE3 isoform, APOE, CYS112 and ARG158 -107741#0001
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  54. ↑ Damoiseaux, Jessica S.; Seeley, William W.; Zhou, Juan; Shirer, William R.; Coppola, Giovanni; Karydas, Anna; Rosen, Howard J.; Miller, Bruce L.; Kramer, Joel H. (2012-06-13). "Gender Modulates the APOE ε4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels". Journal of Neuroscience. 32 (24): 8254–62. doi:10.1523/JNEUROSCI.0305-12.2012. ISSN 0270-6474. PMC 3394933. PMID 22699906.
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  57. ↑ Wozniak MA, Riley EM, Itzhaki RF (March 2004). "Apolipoprotein E polymorphisms and risk of malaria". Journal of Medical Genetics. 41 (3): 145–46. doi:10.1136/jmg.2003.014613. PMC 1735716. PMID 14985370.
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  59. ↑ 59.0 59.1 Huebbe P, Rimbach G (2017). "Evolution of human apolipoprotein E (APOE) isoforms: Gene structure, protein function and interaction with dietary factors". Ageing Research Reviews. 37: 146–61. doi:10.1016/j.arr.2017.06.002. PMID 28647612.
  60. ↑ McIntosh AM, Bennett C, Dickson D, Anestis SF, Watts DP, Webster TH, Fontenot MB, Bradley BJ (2012). "The apolipoprotein E (APOE) gene appears functionally monomorphic in chimpanzees (Pan troglodytes)". PLOS One. 7 (10): e47760. doi:10.1371/journal.pone.0047760. PMC 3480407. PMID 23112842.
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Further reading

External links

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