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Gene Review

APOE  -  apolipoprotein E

Homo sapiens

Synonyms: AD2, APO-E, Apo-E, Apolipoprotein E, LDLCQ5, ...
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Disease relevance of APOE  

  • CONCLUSIONS: These preliminary findings suggest that possession of an APOE epsilon4 allele may be associated with increased severity of chronic neurologic deficits in high-exposure boxers [1].
  • INTERPRETATION: Our findings show a significant genetic association of APOE polymorphism with outcome after head injury supporting the hypothesis of a genetically determined influence [2].
  • 17 (57%) of 30 patients with APOE epsilon4 had an unfavourable outcome (dead, vegetative state, or severe disability) compared with 16 (27%) of the 59 patients without APOE epsilon4 (p=0.006) [2].
  • Polymorphisms in the SAA2 or APOE gene did not appear to influence susceptibility to renal amyloidosis [3].
  • In addition, we have isolated a single lambda phage carrying both APOC1 and part of APOE [4].

Psychiatry related information on APOE


High impact information on APOE


Chemical compound and disease context of APOE


Biological context of APOE

  • We have also identified a unique combination of the ACT/AA and APOE 4/4 genotypes as a potential susceptibility marker for AD, as its frequency was 1/17 in the AD group compared to 1/313 in the general population control [20].
  • An earlier age at onset has also been demonstrated in familial AD patients with mutations in the amyloid precursor protein (APP) gene (APP717 and APP670/671)13 carrying the APOE epsilon-4 allele compared to those who do not, but not in familial AD patients with APP692 or 693 mutations, or in chromosome 14-linked familial AD patients [21].
  • RESULTS: Overall, patients with dementia and stroke had a higher APOE epsilon4 allele frequency than controls [6].
  • Compared with APOE epsilon3 homozygote individuals, APOE epsilon4 homozygotes had a 7-fold increased risk of dementia with stroke (OR=6.9; 95% CI, 1.6-29.4), while APOE epsilon4 heterozygotes had nearly a 2-fold increase in risk (OR=1.8; 95% CI, 1.2-2.7) [6].
  • Genetic linkage and association studies have also shown that the epsilon4 allele of the apolipoprotein E (APOE) gene increases risk for AD in a dose-dependent manner in both familial and sporadic forms of AD and may account for as much as 50% of the attributable risk [22].

Anatomical context of APOE


Associations of APOE with chemical compounds

  • The identification of a variant of the apolipoprotein E (APOE) gene as a major genetic risk factor for AD is also consistent with a role for cholesterol in the pathogenesis of AD [24].
  • CONCLUSIONS: In cognitively intact, older adults, the effect of the APOE epsilon4 allele is not necessarily seen in the immediate response to benzodiazepine challenge [7].
  • APOE/epsilon 4 also significantly contributed to a 2.9% increase of total cholesterol, 11.8% increase of triglyceride and 3.2% of decrease of high-density lipoprotein-cholesterol [17].
  • The epsilon4 allele of APOE is one of three (epsilon2 epsilon3 and epsilon4) common alleles generated by cysteine/arginine substitutions at two polymorphic sites [25].
  • Also, very modest genotype-phenotype associations were observed between APOE genotype (P = 0.016) and plasma low-density lipoprotein cholesterol concentration and between FABP2 genotype and plasma 2-h postprandial, glucose concentration (P = 0.048) [26].

Physical interactions of APOE


Co-localisations of APOE


Regulatory relationships of APOE


Other interactions of APOE


Analytical, diagnostic and therapeutic context of APOE


  1. Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. Jordan, B.D., Relkin, N.R., Ravdin, L.D., Jacobs, A.R., Bennett, A., Gandy, S. JAMA (1997) [Pubmed]
  2. Association of apolipoprotein E polymorphism with outcome after head injury. Teasdale, G.M., Nicoll, J.A., Murray, G., Fiddes, M. Lancet (1997) [Pubmed]
  3. Identification of MEFV-independent modifying genetic factors for familial Mediterranean fever. Cazeneuve, C., Ajrapetyan, H., Papin, S., Roudot-Thoraval, F., Geneviève, D., Mndjoyan, E., Papazian, M., Sarkisian, A., Babloyan, A., Boissier, B., Duquesnoy, P., Kouyoumdjian, J.C., Girodon-Boulandet, E., Grateau, G., Sarkisian, T., Amselem, S. Am. J. Hum. Genet. (2000) [Pubmed]
  4. Regional mapping of human chromosome 19: organization of genes for plasma lipid transport (APOC1, -C2, and -E and LDLR) and the genes C3, PEPD, and GPI. Lusis, A.J., Heinzmann, C., Sparkes, R.S., Scott, J., Knott, T.J., Geller, R., Sparkes, M.C., Mohandas, T. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  5. Cognitive change and the APOE epsilon 4 allele. Deary, I.J., Whiteman, M.C., Pattie, A., Starr, J.M., Hayward, C., Wright, A.F., Carothers, A., Whalley, L.J. Nature (2002) [Pubmed]
  6. Apolipoprotein E epsilon4 and the risk of dementia with stroke. A population-based investigation. Slooter, A.J., Tang, M.X., van Duijn, C.M., Stern, Y., Ott, A., Bell, K., Breteler, M.M., Van Broeckhoven, C., Tatemichi, T.K., Tycko, B., Hofman, A., Mayeux, R. JAMA (1997) [Pubmed]
  7. Apolipoprotein E epsilon4 allele and lorazepam effects on memory in high-functioning older adults. Pomara, N., Willoughby, L., Wesnes, K., Greenblatt, D.J., Sidtis, J.J. Arch. Gen. Psychiatry (2005) [Pubmed]
  8. APOE-epsilon4 and APOE -491A polymorphisms in individuals with subjective memory loss. Laws, S.M., Clarnette, R.M., Taddei, K., Martins, G., Paton, A., Hallmayer, J., Almeida, O.P., Groth, D.M., Gandy, S.E., Förstl, H., Martins, R.N. Mol. Psychiatry (2002) [Pubmed]
  9. Apolipoprotein E epsilon4 and age at onset of sporadic and familial Alzheimer disease in Caribbean Hispanics. Olarte, L., Schupf, N., Lee, J.H., Tang, M.X., Santana, V., Williamson, J., Maramreddy, P., Tycko, B., Mayeux, R. Arch. Neurol. (2006) [Pubmed]
  10. Better memory and neural efficiency in young apolipoprotein E epsilon4 carriers. Mondadori, C.R., de Quervain, D.J., Buchmann, A., Mustovic, H., Wollmer, M.A., Schmidt, C.F., Boesiger, P., Hock, C., Nitsch, R.M., Papassotiropoulos, A., Henke, K. Cereb. Cortex (2007) [Pubmed]
  11. Apolipoprotein E gene polymorphism, total plasma cholesterol level, and Parkinson disease dementia. Jasinska-Myga, B., Opala, G., Goetz, C.G., Tustanowski, J., Ochudlo, S., Gorzkowska, A., Tyrpa, J. Arch. Neurol. (2007) [Pubmed]
  12. Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study. Irie, F., Fitzpatrick, A.L., Lopez, O.L., Kuller, L.H., Peila, R., Newman, A.B., Launer, L.J. Arch. Neurol. (2008) [Pubmed]
  13. A "dock, lock, and latch" structural model for a staphylococcal adhesin binding to fibrinogen. Ponnuraj, K., Bowden, M.G., Davis, S., Gurusiddappa, S., Moore, D., Choe, D., Xu, Y., Hook, M., Narayana, S.V. Cell (2003) [Pubmed]
  14. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. O'Donnell, H.C., Rosand, J., Knudsen, K.A., Furie, K.L., Segal, A.Z., Chiu, R.I., Ikeda, D., Greenberg, S.M. N. Engl. J. Med. (2000) [Pubmed]
  15. Patterns of brain activation in people at risk for Alzheimer's disease. Bookheimer, S.Y., Strojwas, M.H., Cohen, M.S., Saunders, A.M., Pericak-Vance, M.A., Mazziotta, J.C., Small, G.W. N. Engl. J. Med. (2000) [Pubmed]
  16. Specific regional transcription of apolipoprotein E in human brain neurons. Xu, P.T., Gilbert, J.R., Qiu, H.L., Ervin, J., Rothrock-Christian, T.R., Hulette, C., Schmechel, D.E. Am. J. Pathol. (1999) [Pubmed]
  17. Epsilon 4 allele of apolipoprotein E gene associates with lower blood pressure in young Japanese subjects: the Suita Study. Katsuya, T., Baba, S., Ishikawa, K., Mannami, T., Fu, Y., Inamoto, N., Asai, T., Fukuda, M., Higaki, J., Ogata, J., Ogihara, T. J. Hypertens. (2002) [Pubmed]
  18. Modeling the influence of APOC3, APOE, and TNF polymorphisms on the risk of antiretroviral therapy-associated lipid disorders. Tarr, P.E., Taffé, P., Bleiber, G., Furrer, H., Rotger, M., Martinez, R., Hirschel, B., Battegay, M., Weber, R., Vernazza, P., Bernasconi, E., Darioli, R., Rickenbach, M., Ledergerber, B., Telenti, A. J. Infect. Dis. (2005) [Pubmed]
  19. Genetic variation analysis in parkinson disease patients with and without hallucinations: case-control study. Goetz, C.G., Burke, P.F., Leurgans, S., Berry-Kravis, E., Blasucci, L.M., Raman, R., Zhou, L. Arch. Neurol. (2001) [Pubmed]
  20. APOE*4-associated Alzheimer's disease risk is modified by alpha 1-antichymotrypsin polymorphism. Kamboh, M.I., Sanghera, D.K., Ferrell, R.E., DeKosky, S.T. Nat. Genet. (1995) [Pubmed]
  21. Genetic association of the very low density lipoprotein (VLDL) receptor gene with sporadic Alzheimer's disease. Okuizumi, K., Onodera, O., Namba, Y., Ikeda, K., Yamamoto, T., Seki, K., Ueki, A., Nanko, S., Tanaka, H., Takahashi, H., Oyanagi, K., Mizusawa, H., Kanazawa, I., Tsuji, S. Nat. Genet. (1995) [Pubmed]
  22. Exploring the etiology of Alzheimer disease using molecular genetics. Lendon, C.L., Ashall, F., Goate, A.M. JAMA (1997) [Pubmed]
  23. Microglial activation in Alzheimer disease: Association with APOE genotype. Egensperger, R., Kösel, S., von Eitzen, U., Graeber, M.B. Brain Pathol. (1998) [Pubmed]
  24. Alzheimer's disease: the cholesterol connection. Puglielli, L., Tanzi, R.E., Kovacs, D.M. Nat. Neurosci. (2003) [Pubmed]
  25. Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription. Laws, S.M., Hone, E., Gandy, S., Martins, R.N. J. Neurochem. (2003) [Pubmed]
  26. Are Canadian Inuit at increased genetic risk for coronary heart disease? Hegele, R.A., Young, T.K., Connelly, P.W. J. Mol. Med. (1997) [Pubmed]
  27. Apolipoprotein E binds to and potentiates the biological activity of ciliary neurotrophic factor. Gutman, C.R., Strittmatter, W.J., Weisgraber, K.H., Matthew, W.D. J. Neurosci. (1997) [Pubmed]
  28. Lipoprotein lipase induces catabolism of normal triglyceride-rich lipoproteins via the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor in vitro. A process facilitated by cell-surface proteoglycans. Chappell, D.A., Fry, G.L., Waknitz, M.A., Muhonen, L.E., Pladet, M.W., Iverius, P.H., Strickland, D.K. J. Biol. Chem. (1993) [Pubmed]
  29. NMR structure and dynamics of a receptor-active apolipoprotein E peptide. Raussens, V., Slupsky, C.M., Ryan, R.O., Sykes, B.D. J. Biol. Chem. (2002) [Pubmed]
  30. Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis. Carter, C.J. Neurochem. Int. (2007) [Pubmed]
  31. Variants of CYP46A1 may interact with age and APOE to influence CSF Abeta42 levels in Alzheimer's disease. Johansson, A., Katzov, H., Zetterberg, H., Feuk, L., Johansson, B., Bogdanovic, N., Andreasen, N., Lenhard, B., Brookes, A.J., Pedersen, N.L., Blennow, K., Prince, J.A. Hum. Genet. (2004) [Pubmed]
  32. Expression of differential immune factors in temporal cortex and cerebellum: the role of alpha-1-antichymotrypsin, apolipoprotein E, and reactive glia in the progression of Alzheimer's disease. Styren, S.D., Kamboh, M.I., DeKosky, S.T. J. Comp. Neurol. (1998) [Pubmed]
  33. Astrocyte-apolipoprotein E associations in senile plaques in Alzheimer disease and vascular lesions: a regional immunohistochemical study. Shao, Y., Gearing, M., Mirra, S.S. J. Neuropathol. Exp. Neurol. (1997) [Pubmed]
  34. No association between apolipoprotein E epsilon4 allele and the age of onset in type I familial amyloid polyneuropathy. Satoh, S., Tokuda, T., Ikeda, S., Sekijima, Y., Yanagisawa, N., Hidaka, H., Kametani, F. Neurosci. Lett. (1996) [Pubmed]
  35. Apolipoprotein A-I-stimulated apolipoprotein E secretion from human macrophages is independent of cholesterol efflux. Kockx, M., Rye, K.A., Gaus, K., Quinn, C.M., Wright, J., Sloane, T., Sviridov, D., Fu, Y., Sullivan, D., Burnett, J.R., Rust, S., Assmann, G., Anantharamaiah, G.M., Palgunachari, M.N., Katz, S.L., Phillips, M.C., Dean, R.T., Jessup, W., Kritharides, L. J. Biol. Chem. (2004) [Pubmed]
  36. Apolipoprotein E genotype and deposits of Abeta40 and Abeta42 in Alzheimer disease. McNamara, M.J., Gomez-Isla, T., Hyman, B.T. Arch. Neurol. (1998) [Pubmed]
  37. Hepatic triglyceride lipase promotes low density lipoprotein receptor-mediated catabolism of very low density lipoproteins in vitro. Medh, J.D., Bowen, S.L., Fry, G.L., Ruben, S., Hill, J., Wong, H., Chappell, D.A. J. Lipid Res. (1999) [Pubmed]
  38. Alpha-1 antichymotrypsin and alpha-2 macroglobulin gene polymorphisms are not associated with Korean late-onset Alzheimer's disease. Ki, C.S., Na, D.L., Kim, H.J., Kim, J.W. Neurosci. Lett. (2001) [Pubmed]
  39. Apolipoprotein E genotype regulates amyloid-beta cytotoxicity. Wilhelmus, M.M., Otte-Höller, I., Davis, J., Van Nostrand, W.E., de Waal, R.M., Verbeek, M.M. J. Neurosci. (2005) [Pubmed]
  40. Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Strittmatter, W.J., Saunders, A.M., Goedert, M., Weisgraber, K.H., Dong, L.M., Jakes, R., Huang, D.Y., Pericak-Vance, M., Schmechel, D., Roses, A.D. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  41. Apolipoprotein E-promoter single-nucleotide polymorphisms affect the phenotype of primary open-angle glaucoma and demonstrate interaction with the myocilin gene. Copin, B., Brézin, A.P., Valtot, F., Dascotte, J.C., Béchetoille, A., Garchon, H.J. Am. J. Hum. Genet. (2002) [Pubmed]
  42. Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. Zareparsi, S., Buraczynska, M., Branham, K.E., Shah, S., Eng, D., Li, M., Pawar, H., Yashar, B.M., Moroi, S.E., Lichter, P.R., Petty, H.R., Richards, J.E., Abecasis, G.R., Elner, V.M., Swaroop, A. Hum. Mol. Genet. (2005) [Pubmed]
  43. Apolipoprotein E-epsilon 4 protects against severe liver disease caused by hepatitis C virus. Wozniak, M.A., Itzhaki, R.F., Faragher, E.B., James, M.W., Ryder, S.D., Irving, W.L. Hepatology (2002) [Pubmed]
  44. Multiple, diverse senile plaque-associated proteins are ligands of an apolipoprotein E receptor, the alpha 2-macroglobulin receptor/low-density-lipoprotein receptor-related protein. Rebeck, G.W., Harr, S.D., Strickland, D.K., Hyman, B.T. Ann. Neurol. (1995) [Pubmed]
  45. Apolipoprotein E: risk factor for Alzheimer disease. Tsai, M.S., Tangalos, E.G., Petersen, R.C., Smith, G.E., Schaid, D.J., Kokmen, E., Ivnik, R.J., Thibodeau, S.N. Am. J. Hum. Genet. (1994) [Pubmed]
  46. Apolipoprotein E epsilon 4 is associated with rapid progression of multiple sclerosis. Fazekas, F., Strasser-Fuchs, S., Kollegger, H., Berger, T., Kristoferitsch, W., Schmidt, H., Enzinger, C., Schiefermeier, M., Schwarz, C., Kornek, B., Reindl, M., Huber, K., Grass, R., Wimmer, G., Vass, K., Pfeiffer, K.H., Hartung, H.P., Schmidt, R. Neurology (2001) [Pubmed]
  47. APOE polymorphism and the progression of diabetic nephropathy in Japanese subjects with type 2 diabetes: results of a prospective observational follow-up study. Araki, S., Koya, D., Makiishi, T., Sugimoto, T., Isono, M., Kikkawa, R., Kashiwagi, A., Haneda, M. Diabetes Care (2003) [Pubmed]
  48. Biological and genetic determinants of serum apoC-III concentration: reference limits from the Stanislas Cohort. Tilly, P., Sass, C., Vincent-Viry, M., Aguillon, D., Siest, G., Visvikis, S. J. Lipid Res. (2003) [Pubmed]
  49. Apolipoprotein E and dementia in Parkinson disease: a meta-analysis. Huang, X., Chen, P., Kaufer, D.I., Tröster, A.I., Poole, C. Arch. Neurol. (2006) [Pubmed]
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