In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing T cell proliferation, macrophage functioning regulation, lipid antigen presentation facilitation (by CD1)  to natural killer T cell as well as modulation of inflammation and oxidation.
ApoE is polymorphic, with three major isoforms: ApoE2 (cys112, cys158), ApoE3 (cys112, arg158), and ApoE4 (arg112, arg158). Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158, these differences alter apoE structure and function. These have physiological consequences:
E2 (rs7412) is found in approximately 7 percent of the population. This variant of the apoprotein binds poorly to cell surface receptors while E3 and E4 bind well. 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 disordertype 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). E2 has also been implicated in Parkinson's disease. E2 is no longer associated with Parkinson disease in a larger population association study. 
E3 (rs429358) is found in approximately 79 percent of the population. It is considered the "neutral" Apo E genotype.
The E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer disease (AD) in a variety of ethnic groups. Caucasian and Japanese carriers of 2 E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. While the exact mechanism of how E4 causes such dramatic effects remains to be fully determined, evidence has been presented suggesting an interaction with amyloid. Alzheimer disease is characterized by build-ups of aggregates of the peptidebeta-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 catalyzing these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.
The pivotal role of ApoE in AD was first identified through linkage analysis by Margaret Pericak-Vance while working in the Roses lab at Duke University Linkage studies were followed by association analysis confirming the role of the ApoE4 allele as a strong genetic risk factor for AD.
Although 40-65% of AD patients have at least one copy of the 4 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 e4 alleles have up to 20 times the risk of developing AD. There is also evidence that the ApoE2 allele may serve a protective role in AD. Thus, the genotype most at risk for Alzheimer disease and at an earlier age is ApoE 4,4. The ApoE 3,4 genotype is at increased risk, though not to the degree that those homozygous for ApoE 4 are. The genotype ApoE 3,3 is considered at normal risk for Alzheimer disease. The genotype ApoE 2,3 is considered at lower risk for Alzheimer disease. Interestingly, people with both a copy of the 2 allele and the 4 allele, ApoE 2,4, are at normal risk, similar to the ApoE 3,3 genotype.
^Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P (2001). "A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis". Mol Cell7 (1): 161–71. doi:10.1016/S1097-2765(01)00164-2. PMID11172721.
^Eisenberg DTA, Kuzawa CW, Hayes MG. (2010). "Worldwide allele frequencies of the human apoliprotein E (APOE) gene: climate, local adaptations and evolutionary history". American Journal of Physical Anthropology143 (1): 100–111. doi:10.1002/ajpa.21298. PMID20734437.
^Weisgraber KH, Innerarity TL, Mahley RW. (1982). "Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site". J. Biol. Chem.257 (5): 2518–21. PMID6277903.
^Breslow J.L., Zannis V.I., SanGiacomo T.R., Third J.L., Tracy T., Glueck C.J. (1982). "Studies of familial type III hyperlipoproteinemia using as a genetic marker the apoE phenotype E2/2". J. Lipid Res.23 (8): 1224–1235. PMID7175379.
^Civeira F., Pocovi M., Cenarro A., Casao E., Vilella E., Joven J., Gonzalez J., Garcia-Otin A.L., Ordovas J.M. Apo E variants in patients with type III hyperlipoproteinemia. (1996). "Apo E variants in patients with type III hyperlipoproteinemia". Atherosclerosis127 (2): 273–282. doi:10.1016/S0021-9150(96)05969-2. PMID9125318.
^Federoff M1, Jimenez-Rolando B, Nalls MA, Singleton AB. (2012). "A large study reveals no association between APOE and Parkinson's disease.". Neurobiol Dis.46 (2): 389–92. doi:10.1016/j.nbd.2012.02.002. PMID22349451.
^ abCorder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993). "Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families". Science261 (5123): 921–3. doi:10.1126/science.8346443. PMID8346443.
^Burt TD, Agan BK, Marconi VC, He W, Kulkarni H, Mold JE, Cavrois M, Huang Y, Mahley RW, Dolan MJ, McCune JM, Ahuja SK. (2008). "Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression". Proceedings of the National Academy of Sciences of the United States of America105 (25): 8718–23. doi:10.1073/pnas.0803526105. PMID18562290.
^Chapman J, Vinokurov S, Achiron A, Karussis DM, Mitosek-Szewczyk K, Birnbaum M, Michaelson DM, Korczyn AD (2001). "APOE genotype is a major predictor of long-term progression of disability in MS". Neurology56 (3): 312–6. doi:10.1212/wnl.56.3.312. PMID11171894.
^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; Multiple Sclerosis Genetics Group (2002). "Association of polymorphisms in the apolipoprotein E region with susceptibility to and progression of multiple sclerosis". American Journal of Human Genetics70 (3): 708–17. doi:10.1086/339269. PMID11836653.
^Friedman G, Froom P, Sazbon L, Grinblatt I, Shochina M, Tsenter J, Babaey S, Yehuda B, Groswasser Z (1999). "Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury". Neurology52 (2): 244–8. doi:10.1212/wnl.52.2.244. PMID9932938.
^McCarron MO, Delong D, Alberts MJ. (1999). "APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis". Neurology53 (6): 1308–11. doi:10.1212/wnl.53.6.1308. PMID10522889.
^Kadotani H, Kadotani T, Young T, Peppard PE, Finn L, Colrain IM, Murphy GM Jr, Mignot E (2001). "Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults". JAMA285 (22): 2888–90. doi:10.1001/jama.285.22.2888. PMID11401610.
^Gottlieb DJ, DeStefano AL, Foley DJ, Mignot E, Redline S, Givelber RJ, Young T. (2004). "APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study.". Neurology63 (4): 664–8. doi:10.1212/01.wnl.0000134671.99649.32. PMID15326239.
^Sadigh-Eteghad S, Talebi M, Farhoudi M (2012). "Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer’s disease, A meta-analysis". Neurosciences (Riyadh)17 (4): 321–6. PMID23022896.
^Wisniewski T, Frangione B (1992). "Apolipoprotein E: A pathological chaperone protein in patients with cerebral and systemic amyloid". Neurosci. Lett.135 (2): 235–238. doi:10.1016/0304-3940(92)90444-C. PMID1625800.
^Howland DS, Trusko SP, Savage MJ, Reaume AG, Lang DM, Hirsch JD, Maeda N, Siman R, Greenberg BD, Scott RW, Flood DG (June 1998). "Modulation of secreted beta-amyloid precursor protein and amyloid beta-peptide in brain by cholesterol". J. Biol. Chem.273 (26): 16576–82. doi:10.1074/jbc.273.26.16576. PMID9632729.
^Lepara O, Valjevac A, Alajbegović A, Zaćiragić A, Nakas-Ićindić E (August 2009). "Decreased serum lipids in patients with probable Alzheimer's disease". Bosn J Basic Med Sci9 (3): 215–20. PMID19754476.
^Farrer L.A., Cupples L.A., Haines J.L., Hyman B., Kukull W.A., Mayeux R., Myers R.H., Pericak-Vance M.A., Risch N., van Duijn C.N. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. (1997). JAMA278: 1349–1356. doi:10.1001/jama.1997.03550160069041. PMID9343467.
Gunzburg MJ, Perugini MA, Howlett GJ. (2007). "Structural basis for the recognition and cross-linking of amyloid fibrils by human apolipoprotein E". J. Biol. Chem.282 (49): 35831–41. doi:10.1074/jbc.M706425200. PMID17916554.
Bocksch L, Stephens T, Lucas A, Singh B (2003). "Apolipoprotein E: possible therapeutic target for atherosclerosis". Current drug targets. Cardiovascular & haematological disorders1 (2): 93–106. doi:10.2174/1568006013337944. PMID12769659.
Mahley RW, Ji ZS (1999). "Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E". J. Lipid Res.40 (1): 1–16. PMID9869645.
Beffert U, Danik M, Krzywkowski P, et al. (1998). "The neurobiology of apolipoproteins and their receptors in the CNS and Alzheimer's disease". Brain Res. Brain Res. Rev.27 (2): 119–42. doi:10.1016/S0165-0173(98)00008-3. PMID9622609.
Roses AD, Einstein G, Gilbert J, et al. (1996). "Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism". Annals of the New York Academy of Sciences777: 146–57. doi:10.1111/j.1749-6632.1996.tb34413.x. PMID8624078.
de Knijff P, van den Maagdenberg AM, Frants RR, Havekes LM (1995). "Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels". Hum. Mutat.4 (3): 178–94. doi:10.1002/humu.1380040303. PMID7833947.