apolipoprotein E

Apolipoproteins are not unique to mammals. Many terrestrial and marine vertebrates have versions of them.{{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 = 8622–8627 | date = August 1997 | pmid = 9238027 | pmc = 23048 | doi = 10.1073/pnas.94.16.8622 | doi-access = free | bibcode = 1997PNAS...94.8622B }} It is believed that APOE arose via gene duplications of APOC1 before the fish–tetrapod split ca. 400 million years ago. Proteins similar in function have been found in choanoflagellates, suggesting that they are a very old class of proteins predating the dawn of all living animals.{{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 | pages = 146–161 | date = August 2017 | pmid = 28647612 | doi = 10.1016/j.arr.2017.06.002 | s2cid = 3758905 }}

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 which had no effect on protein function (V174L, A18T, A135V). The fourth substitution (T61R) traded a threonine for an arginine altering the protein's functionality. This substitution occurred somewhere in the 6 million year gap between the primate–human split and the Denisovan–human split, since exactly the same substitutions were found in Denisovan APOE.{{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 | doi-access = free | bibcode = 2012PLoSO...747760M }}

About 220,000 years ago, a cysteine to arginine substitution took place at amino acid 112 (Cys112Arg) of the APOE4 gene, and this resulted in the E3 allele. Finally, 80,000 years ago, another arginine to cysteine substitution at amino acid 158 (Arg158Cys) of the APOE3 gene created the E2 allele.{{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 | date = March 2004 | pmid = 15101252 | doi = 10.1086/381662 | s2cid = 14225962 }}

The gene, APOE, is mapped to chromosome 19 in a cluster with the apolipoprotein C1 (APOC1) gene and the apolipoprotein C2 (APOC2) gene. The APOE gene consists of four exons and three introns, totaling 3597 base pairs. APOE is transcriptionally activated by the liver X receptor (an important regulator of cholesterol, fatty acid, and glucose homeostasis) and peroxisome proliferator-activated receptor γ, nuclear receptors that form heterodimers with retinoid X receptors.{{cite journal | vauthors = Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P | title = A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis | journal = Molecular Cell | volume = 7 | issue = 1 | pages = 161–171 | date = January 2001 | pmid = 11172721 | doi = 10.1016/S1097-2765(01)00164-2 | doi-access = free }} In melanocytic cells APOE gene expression may be regulated by MITF.{{cite journal | vauthors = Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E | title = Novel MITF targets identified using a two-step DNA microarray strategy | journal = Pigment Cell & Melanoma Research | volume = 21 | issue = 6 | pages = 665–676 | date = December 2008 | pmid = 19067971 | doi = 10.1111/j.1755-148X.2008.00505.x | s2cid = 24698373 | doi-access = free }}

Apoe-E 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.{{cite journal | vauthors = Phillips MC | title = Apolipoprotein E isoforms and lipoprotein metabolism | journal = IUBMB Life | volume = 66 | issue = 9 | pages = 616–623 | date = September 2014 | pmid = 25328986 | doi = 10.1002/iub.1314 | s2cid = 6159310 | doi-access = }}

{{Infobox single nucleotide polymorphism

| rsid = 429358

| name_1 =

| name_2 =

| name_3 =

| gene = ApoE

| chromosome = 19

| region =

| alfred =

| alzgene_geneid =

| alzgene_polyid =

| pdgene_geneid =

| pdgene_polyid =

| szgene_geneid =

| szgene_polyid =

}}

APOE is polymorphic,{{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 | s2cid = 34696595 }}{{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 = 100–111 | date = September 2010 | pmid = 20734437 | doi = 10.1002/ajpa.21298 }} with three major alleles (epsilon 2, epsilon 3, and epsilon 4): APOE-ε2 (cys112, cys158), APOE-ε3 (cys112, arg158), and APOE-ε4 (arg112, arg158).{{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 | date = October 2005 | pmid = 16204452 | pmc = 1243648 | doi = 10.1093/nar/gni155 }} Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158,{{OMIM|107741#0015|APOE3 isoform, hyperlipoproteinemia, type III, autosomal recessive}}{{OMIM|107741#0001|APOE3 isoform, APOE, CYS112 and ARG158}}{{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 | date = April 2006 | pmid = 16603077 | pmc = 1526745 | doi = 10.1186/1744-9081-2-13 | author-link2 = Christopher H. van Dyck | doi-access = free }} these differences alter APOE structure and function.

There are several low-frequency polymorphisms of APOE. APOE5 comes in two subtypes E5f and E5s, based on migration rates. APOE5 E5f and APOE7 combined were found in 2.8% of Japanese males.{{cite journal | vauthors = Yamanouchi Y, Arinami T, Tsuchiya S, Miyazaki R, Takaki H, Takano T, Hamaguchi H | title = Apolipoprotein E5 and E7 in apparently healthy Japanese males: frequencies and relation to plasma lipid levels | journal = The Japanese Journal of Human Genetics | volume = 39 | issue = 3 | pages = 315–324 | date = September 1994 | pmid = 7841442 | doi = 10.1007/BF01874050 | s2cid = 20361600 | doi-access = free }}{{Unreliable medical source|sure=y|reason=Primary|date=December 2022}} APOE7 is a mutation of APOE3 with two lysine residues replacing glutamic acid residues at positions 244 and 245.{{cite journal | vauthors = Dong J, Balestra ME, Newhouse YM, Weisgraber KH | title = Human apolipoprotein E7:lysine mutations in the carboxy-terminal domain are directly responsible for preferential binding to very low density lipoproteins | journal = Journal of Lipid Research | volume = 41 | issue = 11 | pages = 1783–1789 | date = November 2000 | pmid = 11060347 | doi = 10.1016/S0022-2275(20)31971-4 | doi-access = free }}

Much remains to be learned about the APOE isoforms, including the interaction of other protective genes.Sundermann EE, Wang C, Katz M, et al. Cholesteryl ester transfer protein genotype modifies the effect of apolipoprotein ε4 on memory decline in older adults. Neurobiol Aging. 2016;41:200.e7-200.e12. doi:10.1016/j.neurobiolaging.2016.02.006 Indeed, the apolipoprotein ε4 isoform is more protective against cognitive decline than other isoforms in some cases, so caution is advised before making determinant statements about the influence of APOE polymorphisms on cognition, development of Alzheimer's disease, cardiovascular disease, telomere shortening, etc. Many of the studies cited that purport these adverse outcomes are from single studies that have not been replicated and the research is based on unchecked assumptions about this isoform. As of 2007, there was no evidence that APOE polymorphisms influence cognition in younger age groups (other than possible increased episodic memory ability and neural efficiency in younger APOE4 age groups), nor that the APOE4 isoform places individuals at increased risk for any infectious disease.{{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 = 1934–1947 | date = August 2007 | pmid = 17077159 | doi = 10.1093/cercor/bhl103 | doi-access = free | hdl = 20.500.11850/5720 | hdl-access = free }}

However, the association between the APOE4 allele and Alzheimer's disease has been shown to be weaker in minority groups differently compared to their Caucasian counterparts. Hispanics/Latinos and African Americans who were homozygous for the APOE4 allele had 2.2 and 5.7 times the odds, respectively of developing Alzheimer's disease.{{cite journal | vauthors = Huynh RA, Mohan C | title = Alzheimer's Disease: Biomarkers in the Genome, Blood, and Cerebrospinal Fluid | journal = Frontiers in Neurology | volume = 8 | pages = 102 | date = 2017 | pmid = 28373857 | pmc = 5357660 | doi = 10.3389/fneur.2017.00102 | doi-access = free }} The homozygous APOE4 allele has an even stronger effect in East Asian populations, with Japanese populations have 33 times the odds compared to the heterozygous population.{{cite journal | vauthors = Miyashita A, Kikuchi M, Hara N, Ikeuchi T | title = Genetics of Alzheimer's disease: an East Asian perspective | journal = Journal of Human Genetics | volume = 68 | issue = 3 | pages = 115–124 | date = March 2023 | pmid = 35641666 | pmc = 9968656 | doi = 10.1038/s10038-022-01050-z }} Caucasians who were homozygous for the allele had 12.5 times the odds.

As a component of the lipoprotein lipid transport system, APOE facilitates the transport of lipids, fat-soluble vitamins, and cholesterol via the blood. It interacts with the LDL receptor to facilitate endocytosis of VLDL remnants. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen.{{cite book | vauthors = Baars HF, van der Smagt JJ, Doevandans PA | title = Clinical Cardiogenetics | date = 2011 | publisher = Springer | location = London | isbn = 978-1849964715 }} APOE synthesized in the liver associates with HDL which can then distribute it to newly formed VLDL or chylomicron particles to facilitate their eventual uptake by the liver.

In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE.{{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 }} There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved LDLR family.{{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 = 259–270 | date = August 2008 | pmid = 19674510 | doi = 10.1017/S1740925X09990184 }}

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.{{cite journal | vauthors = Sacks FM | title = The crucial roles of apolipoproteins E and C-III in apoB lipoprotein metabolism in normolipidemia and hypertriglyceridemia | journal = Current Opinion in Lipidology | volume = 26 | issue = 1 | pages = 56–63 | date = February 2015 | pmid = 25551803 | pmc = 4371603 | doi = 10.1097/MOL.0000000000000146 }} More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD), immunoregulation, and cognition. Though 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.{{cite 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 = 375–383 | date = August 2015 | pmid = 26073697 | doi = 10.1016/j.neuroscience.2015.06.005 | s2cid = 42716198 }}

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){{cite journal | vauthors = van den Elzen P, Garg S, León L, Brigl M, Leadbetter EA, Gumperz JE, Dascher CC, Cheng TY, Sacks FM, Illarionov PA, Besra GS, Kent SC, Moody DB, Brenner MB | title = Apolipoprotein-mediated pathways of lipid antigen presentation | journal = Nature | volume = 437 | issue = 7060 | pages = 906–910 | date = October 2005 | pmid = 16208376 | doi = 10.1038/nature04001 | s2cid = 3109596 | bibcode = 2005Natur.437..906E }} to natural killer T cell as well as modulation of inflammation and oxidation.{{cite journal | vauthors = Zhang HL, Wu J, Zhu J | title = The role of apolipoprotein E in Guillain-Barré syndrome and experimental autoimmune neuritis | journal = Journal of Biomedicine & Biotechnology | volume = 2010 | pages = 357412 | year = 2010 | pmid = 20182542 | pmc = 2825561 | doi = 10.1155/2010/357412 | doi-access = free }} 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.{{cite journal | vauthors = Braesch-Andersen S, Paulie S, Smedman C, Mia S, Kumagai-Braesch M | title = ApoE production in human monocytes and its regulation by inflammatory cytokines | journal = PLOS ONE | volume = 8 | issue = 11 | pages = e79908 | year = 2013 | pmid = 24244577 | pmc = 3828220 | doi = 10.1371/journal.pone.0079908 | doi-access = free | bibcode = 2013PLoSO...879908B }}

As of 2012, the E4 variant was the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups.{{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 = 321–326 | date = October 2012 | pmid = 23022896 }} However, the E4 variant does not correlate with risk in every population. Nigerian people have the highest observed frequency of the APOE4 allele in world populations,{{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 = 586–591 | date = October 1989 | pmid = 2491016 | pmc = 1683508 }} but AD is rare among them.{{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 | s2cid = 71543885 }} This may be due to their low cholesterol levels.{{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 | s2cid = 35969696 }}{{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 = 149–155 | date = August 2002 | pmid = 12160362 | doi = 10.7326/0003-4819-137-3-200208060-00006 | s2cid = 23780605 }} Caucasian and Japanese carriers of two E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. This may be caused by an interaction with amyloid.{{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 = 235–238 | date = February 1992 | pmid = 1625800 | doi = 10.1016/0304-3940(92)90444-C | s2cid = 8839627 | doi-access = free }} 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.{{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 = 681–693 | date = June 2008 | pmid = 18549781 | pmc = 2493297 | doi = 10.1016/j.neuron.2008.04.010 }}

• {{lay source |template = cite press release|url = https://www.sciencedaily.com/releases/2008/06/080611135123.htm|title = Mechanism Explains Link Between Apolipoprotein E And Alzheimer's Disease|date = June 13, 2008 |website = ScienceDaily }}

Recently, the amyloid hypothesis of Alzheimer's disease has been questioned, and an article in Science claimed that "Just as removing smoke does not extinguish a fire, reducing amyloid plaques may not affect the course of Alzheimer's disease."{{cite journal | vauthors = Thambisetty M, Howard R, Glymour MM, Schneider LS | title = Alzheimer's drugs: Does reducing amyloid work? | journal = Science | volume = 374 | issue = 6567 | pages = 544–545 | date = October 2021 | pmid = 34709898 | doi = 10.1126/science.abl8366 | s2cid = 240152869 | bibcode = 2021Sci...374..544T | url = https://discovery.ucl.ac.uk/id/eprint/10140292/ }} The role that the E4 variant carries can still be fully explained even in the absence of a valid amyloid hypothesis given the fact that reelin signaling emerges to be one of the key processes involved in Alzheimer's disease{{cite journal | vauthors = Kovács KA | title = Relevance of a Novel Circuit-Level Model of Episodic Memories to Alzheimer's Disease | journal = International Journal of Molecular Sciences | volume = 23 | issue = 1 | pages = 462 | date = December 2021 | pmid = 35008886 | pmc = 8745479 | doi = 10.3390/ijms23010462 | doi-access = free }} and the E4 variant is shown to interact with ApoER2, one of the neuronal reelin receptors, thereby obstructing reelin signaling.

Although 40–65% of AD patients have at least one copy of the ε4 allele, APOE4 is not a determinant of the disease. At least one-third of patients with AD are APOE4 negative and some APOE4 homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD.{{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 = 809–817 | date = October 2013 | pmid = 23919769 | pmc = 3995977 | doi = 10.2174/15672050113109990156 }} There is also evidence that the APOE2 allele may serve a protective role in AD.{{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 = 180–184 | date = June 1994 | pmid = 7920638 | doi = 10.1038/ng0694-180 | s2cid = 11137478 }} Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is APOE4,4. Using genotype APOE3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0) and for white populations only, individuals with genotype APOE4,4 have an odds ratio of 14.9 of developing Alzheimer's disease. Individuals with the APOE3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (APOE2,4), have an odds ratio of 2.6. Persons with one copy each of 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.{{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 = 1349–1356 | year = 1997 | pmid = 9343467 | doi = 10.1001/jama.1997.03550160069041 }}

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. Projecting from their data, some researchers have suggested that lowering serum cholesterol levels may reduce a person's risk for Alzheimer's disease, even if they have two ApoE4 alleles, thus reducing the risk from nine or ten times the odds of getting AD down to just two times the odds.

Women are more likely to develop AD than men across most ages and APOE genotypes. Premorbid women with the ε4 allele have significantly more neurological dysfunction than men.{{cite journal | vauthors = Damoiseaux JS, Seeley WW, Zhou J, Shirer WR, Coppola G, Karydas A, Rosen HJ, Miller BL, Kramer JH, Greicius MD | title = Gender modulates the APOE ε4 effect in healthy older adults: convergent evidence from functional brain connectivity and spinal fluid tau levels | journal = The Journal of Neuroscience | volume = 32 | issue = 24 | pages = 8254–8262 | date = June 2012 | pmid = 22699906 | pmc = 3394933 | doi = 10.1523/JNEUROSCI.0305-12.2012 }}

APOE-ε4 increases the risk not only for AD but also for dementia in pure alpha-synucleinopathies.{{cite journal | vauthors = Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, Buchman AS, Larson EB, Crane PK, Kaye JA, Kramer P, Woltjer R, Trojanowski JQ, Weintraub D, Chen-Plotkin AS, Irwin DJ, Rick J, Schellenberg GD, Watson GS, Kukull W, Nelson PT, Jicha GA, Neltner JH, Galasko D, Masliah E, Quinn JF, Chung KA, Yearout D, Mata IF, Wan JY, Edwards KL, Montine TJ, Zabetian CP | title = APOE ε4 increases risk for dementia in pure synucleinopathies | journal = JAMA Neurology | volume = 70 | issue = 2 | pages = 223–228 | date = February 2013 | pmid = 23407718 | pmc = 3580799 | doi = 10.1001/jamaneurol.2013.600 }} The influence of APOE-ε4 on hippocampal atrophy was suggested to be more predominant early in the course of AD at milder stages prior to more widespread neurodegeneration.

With the approval of the first disease-modifying therapies for Alzheimer's disease based on monoclonal antibodies against amyloid-beta, which delay disease progression, APOE genotyping has also become important in assessing a patient’s risk of side effects under therapy. In November 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency following a re-examination procedure, adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Leqembi, intended for the treatment of early Alzheimer's disease in apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes.{{cite web | title=Leqembi EPAR | website=European Medicines Agency (EMA) | date=27 February 2025 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/leqembi | access-date=22 March 2025}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. The applicant for this medicinal product is Eisai GmbH.{{cite press release | title=Leqembi recommended for treatment of early Alzheimer's disease | website=European Medicines Agency (EMA) | date=14 November 2024 | url=https://www.ema.europa.eu/en/news/leqembi-recommended-treatment-early-alzheimers-disease | access-date=22 March 2025}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

Knockout mice that lack the apolipoprotein-E gene (APOE^−/−) develop extreme hypercholesterolemia when fed a high-fat diet.{{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 = 641–655 | date = March 2010 | pmid = 20210786 | doi = 10.1042/CS20090488 }}

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.{{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 | pages = 33615 | date = September 2016 | pmid = 27647324 | pmc = 5028887 | doi = 10.1038/srep33615 | bibcode = 2016NatSR...633615K }} Human studies have shown that the APOE2 polymorphism correlates with earlier infection, and APOE3/4 polymorphisms increase likelihood of severe malaria.{{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 = 145–146 | date = March 2004 | pmid = 14985370 | pmc = 1735716 | doi = 10.1136/jmg.2003.014613 }}

Borrelia burgdorferi, the causative agent of Lyme disease, is a host-adapted pathogen that acquires environmental cholesterol to form glycolipids for use in cell membrane maintenance. In one [https://pubmed.ncbi.nlm.nih.gov/25870274/ experiment] in 2015, mice engineered with apoE deficiency were infected with Borrelia spirochetes. The knockout mice suffered from an increased spirochete burden in joints, as well as inflamed ankles, when compared with wild-type mice. This study suggests that apoE deficiency (and potentially other hyperlipidemias) may be a risk factor in the pathogenicity of Lyme disease.

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• {{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 = 157–165 | year = 2004 | pmid = 15181244 | doi = 10.1385/JMN:23:3:157 | s2cid = 14864342 }}
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• {{cite journal | vauthors = Bocksch L, Stephens T, Lucas A, Singh B | title = Apolipoprotein E: possible therapeutic target for atherosclerosis | journal = Current Drug Targets. Cardiovascular & Hematological Disorders | volume = 1 | issue = 2 | pages = 93–106 | date = December 2001 | pmid = 12769659 | doi = 10.2174/1568006013337944 }}
• {{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 = 178–194 | year = 1995 | pmid = 7833947 | doi = 10.1002/humu.1380040303 | s2cid = 41959843 | doi-access = free }}
• {{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 = 35831–35841 | date = December 2007 | pmid = 17916554 | doi = 10.1074/jbc.M706425200 | doi-access = free }}
• {{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 | s2cid = 40135107 }}
• {{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 | s2cid = 28979273 | bibcode = 2004NYASA1019...15I }}
• {{cite journal | vauthors = Kolbe D, da Silva NA, Dose J, Torres GG, Caliebe A, Krause-Kyora B, Nebel A | title = Current allele distribution of the human longevity gene APOE in Europe can mainly be explained by ancient admixture | journal = Aging Cell | volume = 22 | issue = 5 | pages = e13819 | date = May 2023 | pmid = 36951219 | doi = 10.1111/acel.13819 | publisher = Wiley | pmc = 10186601 }}
• {{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 | s2cid = 35607578 }}
• {{cite journal | vauthors = Lambert JC, Amouyel P | title = Genetic heterogeneity of Alzheimer's disease: complexity and advances | journal = Psychoneuroendocrinology | volume = 32 | issue = Suppl 1 | pages = S62–S70 | date = August 2007 | pmid = 17659844 | doi = 10.1016/j.psyneuen.2007.05.015 | s2cid = 8114580 }}
• {{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 = 106–118 | date = February 2013 | pmid = 23296339 | pmc = 3726719 | doi = 10.1038/nrneurol.2012.263 }}
• {{cite journal | vauthors = Mahley RW, Ji ZS | title = Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E | journal = Journal of Lipid Research | volume = 40 | issue = 1 | pages = 1–16 | date = January 1999 | pmid = 9869645 | doi = 10.1016/S0022-2275(20)33334-4 | doi-access = free }}
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• {{cite journal | vauthors = Mahley RW | title = Apolipoprotein E: cholesterol transport protein with expanding role in cell biology | journal = Science | volume = 240 | issue = 4852 | pages = 622–630 | date = April 1988 | pmid = 3283935 | doi = 10.1126/science.3283935 | bibcode = 1988Sci...240..622M }}
• {{cite journal | vauthors = Masterman T, Hillert J | title = The telltale scan: APOE epsilon4 in multiple sclerosis | journal = The Lancet. Neurology | volume = 3 | issue = 6 | pages = 331 | date = June 2004 | pmid = 15157846 | doi = 10.1016/S1474-4422(04)00763-X | s2cid = 54404547 }}
• {{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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• {{cite journal | vauthors = Raber J | title = Role of apolipoprotein E in anxiety | journal = Neural Plasticity | volume = 2007 | pages = 91236 | year = 2007 | pmid = 17710250 | pmc = 1940061 | doi = 10.1155/2007/91236 | doi-access = free }}
• {{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 = 146–157 | date = January 1996 | pmid = 8624078 | doi = 10.1111/j.1749-6632.1996.tb34413.x | s2cid = 9145181 | bibcode = 1996NYASA.777..146R }}
• {{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 = 4725–4727 | date = May 1995 | pmid = 7761390 | pmc = 41779 | doi = 10.1073/pnas.92.11.4725 | doi-access = free | bibcode = 1995PNAS...92.4725S }}
• {{cite journal | vauthors = Utermann G, Pruin N, Steinmetz A | title = Polymorphism of apolipoprotein E. III. Effect of a single polymorphic gene locus on plasma lipid levels in man | journal = Clinical Genetics | volume = 15 | issue = 1 | pages = 63–72 | date = January 1979 | pmid = 759055 | doi = 10.1111/j.1399-0004.1979.tb02028.x | s2cid = 34127430 }}
• {{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 | doi-access = free }}

{{Refend}}

• {{MeshName|Apolipoproteins+E}}
• {{UCSC gene info|APOE}}
• {{PDBe-KB2|P02649|Apolipoprotein E}}

{{PDB Gallery|geneid=348}}

{{Lipoproteins}}

{{Longevity}}

Category:Apolipoproteins

Category:Alzheimer's disease