Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1994 Apr;54(4):643–649.

Apolipoprotein E: risk factor for Alzheimer disease.

M S Tsai 1, E G Tangalos 1, R C Petersen 1, G E Smith 1, D J Schaid 1, E Kokmen 1, R J Ivnik 1, S N Thibodeau 1
PMCID: PMC1918094  PMID: 8128961

Abstract

The apolipoprotein E gene (APOE) has three common alleles (epsilon 2, epsilon 3, and epsilon 4) that determine six genotypes in the general population. In this study, we examined 77 patients with late-onset Alzheimer disease (AD), along with an equal number of age- and sex-matched controls, for an association with the APOE-epsilon 4 allele. We show that the frequency of this allele among AD patients was significantly higher than that among the control population (.351 vs. .130, P = .000006). The genotype frequencies also differed between the two groups (P = .0002), with the APOE-epsilon 4/epsilon 3 genotype being the most common in the AD group and the APOE-epsilon 3/epsilon 3 being the most common in the control group. In the AD group, homozygosity for epsilon 4 was found in nine individuals, whereas none was found in the control group. The odds ratio for AD, when associated with one or two epsilon 4 alleles, was 4.6 (95% confidence interval [CI] 1.9-12.3), while the odds ratio for AD, when associated with heterozygosity for APOE-epsilon 4, was 3.6 (95% CI 1.5-9.8). Finally, the median age at onset among the AD patients decreased from 83 to 78 to 74 years as the number of APOE-epsilon 4 alleles increased from 0 to 1 to 2, respectively (test for trend, P = .001). Our data, which are in agreement with recent reports, suggest that the APOE-epsilon 4 allele is associated with AD and that this allelic variant may be an important risk factor for susceptibility to AD in the general population.

Full text

PDF
643

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Boyles J. K., Pitas R. E., Wilson E., Mahley R. W., Taylor J. M. Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J Clin Invest. 1985 Oct;76(4):1501–1513. doi: 10.1172/JCI112130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boyles J. K., Zoellner C. D., Anderson L. J., Kosik L. M., Pitas R. E., Weisgraber K. H., Hui D. Y., Mahley R. W., Gebicke-Haerter P. J., Ignatius M. J. A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. J Clin Invest. 1989 Mar;83(3):1015–1031. doi: 10.1172/JCI113943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Busciglio J., Gabuzda D. H., Matsudaira P., Yankner B. A. Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):2092–2096. doi: 10.1073/pnas.90.5.2092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Carlsson J., Armstrong V. W., Reiber H., Felgenhauer K., Seidel D. Clinical relevance of the quantification of apolipoprotein E in cerebrospinal fluid. Clin Chim Acta. 1991 Feb 15;196(2-3):167–176. doi: 10.1016/0009-8981(91)90070-s. [DOI] [PubMed] [Google Scholar]
  5. Cauley J. A., Eichner J. E., Kamboh M. I., Ferrell R. E., Kuller L. H. Apo E allele frequencies in younger (age 42-50) vs older (age 65-90) women. Genet Epidemiol. 1993;10(1):27–34. doi: 10.1002/gepi.1370100104. [DOI] [PubMed] [Google Scholar]
  6. Chui H. C., Victoroff J. I., Margolin D., Jagust W., Shankle R., Katzman R. Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer's Disease Diagnostic and Treatment Centers. Neurology. 1992 Mar;42(3 Pt 1):473–480. doi: 10.1212/wnl.42.3.473. [DOI] [PubMed] [Google Scholar]
  7. Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., Roses A. D., Haines J. L., Pericak-Vance M. A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921–923. doi: 10.1126/science.8346443. [DOI] [PubMed] [Google Scholar]
  8. Davignon J., Gregg R. E., Sing C. F. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988 Jan-Feb;8(1):1–21. doi: 10.1161/01.atv.8.1.1. [DOI] [PubMed] [Google Scholar]
  9. Emi M., Wu L. L., Robertson M. A., Myers R. L., Hegele R. A., Williams R. R., White R., Lalouel J. M. Genotyping and sequence analysis of apolipoprotein E isoforms. Genomics. 1988 Nov;3(4):373–379. doi: 10.1016/0888-7543(88)90130-9. [DOI] [PubMed] [Google Scholar]
  10. Flicker C., Ferris S. H., Reisberg B. Mild cognitive impairment in the elderly: predictors of dementia. Neurology. 1991 Jul;41(7):1006–1009. doi: 10.1212/wnl.41.7.1006. [DOI] [PubMed] [Google Scholar]
  11. Haines J. L. The genetics of Alzheimer disease--a teasing problem. Am J Hum Genet. 1991 Jun;48(6):1021–1025. [PMC free article] [PubMed] [Google Scholar]
  12. Hilbich C., Kisters-Woike B., Reed J., Masters C. L., Beyreuther K. Aggregation and secondary structure of synthetic amyloid beta A4 peptides of Alzheimer's disease. J Mol Biol. 1991 Mar 5;218(1):149–163. doi: 10.1016/0022-2836(91)90881-6. [DOI] [PubMed] [Google Scholar]
  13. Hixson J. E., Vernier D. T. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990 Mar;31(3):545–548. [PubMed] [Google Scholar]
  14. Khachaturian Z. S. Diagnosis of Alzheimer's disease. Arch Neurol. 1985 Nov;42(11):1097–1105. doi: 10.1001/archneur.1985.04060100083029. [DOI] [PubMed] [Google Scholar]
  15. Kokmen E., Beard C. M., Offord K. P., Kurland L. T. Prevalence of medically diagnosed dementia in a defined United States population: Rochester, Minnesota, January 1, 1975. Neurology. 1989 Jun;39(6):773–776. doi: 10.1212/wnl.39.6.773. [DOI] [PubMed] [Google Scholar]
  16. Mahley R. W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988 Apr 29;240(4852):622–630. doi: 10.1126/science.3283935. [DOI] [PubMed] [Google Scholar]
  17. Mayeux R., Stern Y., Ottman R., Tatemichi T. K., Tang M. X., Maestre G., Ngai C., Tycko B., Ginsberg H. The apolipoprotein epsilon 4 allele in patients with Alzheimer's disease. Ann Neurol. 1993 Nov;34(5):752–754. doi: 10.1002/ana.410340527. [DOI] [PubMed] [Google Scholar]
  18. McKhann G., Drachman D., Folstein M., Katzman R., Price D., Stadlan E. M. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939–944. doi: 10.1212/wnl.34.7.939. [DOI] [PubMed] [Google Scholar]
  19. Murphy M. The molecular pathogenesis of Alzheimer's disease: clinical prospects. Lancet. 1992 Dec 19;340(8834-8835):1512–1515. doi: 10.1016/0140-6736(92)92765-8. [DOI] [PubMed] [Google Scholar]
  20. Namba Y., Tomonaga M., Kawasaki H., Otomo E., Ikeda K. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 1991 Feb 8;541(1):163–166. doi: 10.1016/0006-8993(91)91092-f. [DOI] [PubMed] [Google Scholar]
  21. Payami H., Kaye J., Heston L. L., Bird T. D., Schellenberg G. D. Apolipoprotein E genotype and Alzheimer's disease. Lancet. 1993 Sep 18;342(8873):738–738. [PubMed] [Google Scholar]
  22. Poirier J., Davignon J., Bouthillier D., Kogan S., Bertrand P., Gauthier S. Apolipoprotein E polymorphism and Alzheimer's disease. Lancet. 1993 Sep 18;342(8873):697–699. doi: 10.1016/0140-6736(93)91705-q. [DOI] [PubMed] [Google Scholar]
  23. Saunders A. M., Schmader K., Breitner J. C., Benson M. D., Brown W. T., Goldfarb L., Goldgaber D., Manwaring M. G., Szymanski M. H., McCown N. Apolipoprotein E epsilon 4 allele distributions in late-onset Alzheimer's disease and in other amyloid-forming diseases. Lancet. 1993 Sep 18;342(8873):710–711. doi: 10.1016/0140-6736(93)91709-u. [DOI] [PubMed] [Google Scholar]
  24. Saunders A. M., Strittmatter W. J., Schmechel D., George-Hyslop P. H., Pericak-Vance M. A., Joo S. H., Rosi B. L., Gusella J. F., Crapper-MacLachlan D. R., Alberts M. J. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993 Aug;43(8):1467–1472. doi: 10.1212/wnl.43.8.1467. [DOI] [PubMed] [Google Scholar]
  25. Strittmatter W. J., Saunders A. M., Schmechel D., Pericak-Vance M., Enghild J., Salvesen G. S., Roses A. D. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977–1981. doi: 10.1073/pnas.90.5.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wisniewski T., Frangione B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett. 1992 Feb 3;135(2):235–238. doi: 10.1016/0304-3940(92)90444-c. [DOI] [PubMed] [Google Scholar]
  27. Wisniewski T., Golabek A., Matsubara E., Ghiso J., Frangione B. Apolipoprotein E: binding to soluble Alzheimer's beta-amyloid. Biochem Biophys Res Commun. 1993 Apr 30;192(2):359–365. doi: 10.1006/bbrc.1993.1423. [DOI] [PubMed] [Google Scholar]
  28. Yankner B. A., Mesulam M. M. Seminars in medicine of the Beth Israel Hospital, Boston. beta-Amyloid and the pathogenesis of Alzheimer's disease. N Engl J Med. 1991 Dec 26;325(26):1849–1857. doi: 10.1056/NEJM199112263252605. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES