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Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2002 Dec;73(6):672–677. doi: 10.1136/jnnp.73.6.672

The apolipoprotein E ε2 allele and decline in episodic memory

R Wilson 1, J Bienias 1, E Berry-Kravis 1, D Evans 1, D Bennett 1
PMCID: PMC1757351  PMID: 12438469

Abstract

Objectives: The apolipoprotein E (apoE) ε4 allele is related to decline in multiple cognitive domains, especially episodic memory, but the effect of the ε2 allele on change in different forms of cognitive function has been difficult to establish.

Methods: Participants are from the Religious Orders Study. At baseline, they were at least 65 years old and free of clinical evidence of dementia. For up to eight years, they underwent annual clinical evaluations that included detailed cognitive function assessment from which previously established summary measures of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability were derived. Growth curve models were used to assess change in each measure and its relation to apoE genotype, controlling for age, sex, education, and baseline level of cognition. Follow up data were available in 669 persons (98% of those eligible). We treated those with the ε3/3 genotype as the reference group (n=425), which was contrasted with ε2 (ε2/2, ε2/3; n=86), and ε4 (ε3/4, ε4/4; n=158) subgroups.

Results: Rate of episodic memory change in the three subgroups significantly differed, with an average annual increase of 0.016 units in the ε2 subgroup and annual decreases of 0.022 units in those with ε3/3 and of 0.073 units in the ε4 subgroup. The ε2 subgroup did not differ from those with ε3/3 in rate of decline in other cognitive systems. The ε4 subgroup declined more rapidly than those with ε3/3 in semantic memory and perceptual speed but not in working memory or visuospatial ability.

Conclusion: Possession of one or more apoE ε2 alleles is associated with reduced decline in episodic memory in older persons.

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Selected References

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  1. Albert M., Smith L. A., Scherr P. A., Taylor J. O., Evans D. A., Funkenstein H. H. Use of brief cognitive tests to identify individuals in the community with clinically diagnosed Alzheimer's disease. Int J Neurosci. 1991 Apr;57(3-4):167–178. doi: 10.3109/00207459109150691. [DOI] [PubMed] [Google Scholar]
  2. Arnold S. E., Joo E., Martinoli M. G., Roy N., Trojanowski J. Q., Gur R. E., Cannon T., Price R. A. Apolipoprotein E genotype in schizophrenia: frequency, age of onset, and neuropathologic features. Neuroreport. 1997 Apr 14;8(6):1523–1526. doi: 10.1097/00001756-199704140-00040. [DOI] [PubMed] [Google Scholar]
  3. Bennett D. A., Wilson R. S., Schneider J. A., Evans D. A., Beckett L. A., Aggarwal N. T., Barnes L. L., Fox J. H., Bach J. Natural history of mild cognitive impairment in older persons. Neurology. 2002 Jul 23;59(2):198–205. doi: 10.1212/wnl.59.2.198. [DOI] [PubMed] [Google Scholar]
  4. Cooper J. A., Sagar H. J., Jordan N., Harvey N. S., Sullivan E. V. Cognitive impairment in early, untreated Parkinson's disease and its relationship to motor disability. Brain. 1991 Oct;114(Pt 5):2095–2122. doi: 10.1093/brain/114.5.2095. [DOI] [PubMed] [Google Scholar]
  5. Corder E. H., Saunders A. M., Risch N. J., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Jr, Rimmler J. B., Locke P. A., Conneally P. M., Schmader K. E. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994 Jun;7(2):180–184. doi: 10.1038/ng0694-180. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Evans D. A., Beckett L. A., Field T. S., Feng L., Albert M. S., Bennett D. A., Tycko B., Mayeux R. Apolipoprotein E epsilon4 and incidence of Alzheimer disease in a community population of older persons. JAMA. 1997 Mar 12;277(10):822–824. [PubMed] [Google Scholar]
  8. 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. M. 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. JAMA. 1997 Oct 22;278(16):1349–1356. [PubMed] [Google Scholar]
  9. Haan M. N., Shemanski L., Jagust W. J., Manolio T. A., Kuller L. The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA. 1999 Jul 7;282(1):40–46. doi: 10.1001/jama.282.1.40. [DOI] [PubMed] [Google Scholar]
  10. Helkala E. L., Koivisto K., Hanninen T., Vanhanen M., Kervinen K., Kuusisto J., Mykkanen L., Kesaniemi Y. A., Laakso M., Riekkinen P., Sr Memory functions in human subjects with different apolipoprotein E phenotypes during a 3-year population-based follow-up study. Neurosci Lett. 1996 Feb 9;204(3):177–180. doi: 10.1016/0304-3940(96)12348-x. [DOI] [PubMed] [Google Scholar]
  11. Henderson A. S., Easteal S., Jorm A. F., Mackinnon A. J., Korten A. E., Christensen H., Croft L., Jacomb P. A. Apolipoprotein E allele epsilon 4, dementia, and cognitive decline in a population sample. Lancet. 1995 Nov 25;346(8987):1387–1390. doi: 10.1016/s0140-6736(95)92405-1. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Hyman B. T., Gomez-Isla T., Briggs M., Chung H., Nichols S., Kohout F., Wallace R. Apolipoprotein E and cognitive change in an elderly population. Ann Neurol. 1996 Jul;40(1):55–66. doi: 10.1002/ana.410400111. [DOI] [PubMed] [Google Scholar]
  14. Laird N. M., Ware J. H. Random-effects models for longitudinal data. Biometrics. 1982 Dec;38(4):963–974. [PubMed] [Google Scholar]
  15. Mayeux R., Small S. A., Tang M., Tycko B., Stern Y. Memory performance in healthy elderly without Alzheimer's disease: effects of time and apolipoprotein-E. Neurobiol Aging. 2001 Jul-Aug;22(4):683–689. doi: 10.1016/s0197-4580(01)00223-8. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Myers R. H., Schaefer E. J., Wilson P. W., D'Agostino R., Ordovas J. M., Espino A., Au R., White R. F., Knoefel J. E., Cobb J. L. Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study. Neurology. 1996 Mar;46(3):673–677. doi: 10.1212/wnl.46.3.673. [DOI] [PubMed] [Google Scholar]
  18. Ordovas J. M., Litwack-Klein L., Wilson P. W., Schaefer M. M., Schaefer E. J. Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms. J Lipid Res. 1987 Apr;28(4):371–380. [PubMed] [Google Scholar]
  19. 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]
  20. Slooter A. J., Cruts M., Kalmijn S., Hofman A., Breteler M. M., Van Broeckhoven C., van Duijn C. M. Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study. Arch Neurol. 1998 Jul;55(7):964–968. doi: 10.1001/archneur.55.7.964. [DOI] [PubMed] [Google Scholar]
  21. Staehelin H. B., Perrig-Chiello P., Mitrache C., Miserez A. R., Perrig W. J. Apolipoprotein E genotypes and cognitive functions in healthy elderly persons. Acta Neurol Scand. 1999 Jul;100(1):53–60. doi: 10.1111/j.1600-0404.1999.tb00723.x. [DOI] [PubMed] [Google Scholar]
  22. Welsh K. A., Butters N., Mohs R. C., Beekly D., Edland S., Fillenbaum G., Heyman A. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part V. A normative study of the neuropsychological battery. Neurology. 1994 Apr;44(4):609–614. doi: 10.1212/wnl.44.4.609. [DOI] [PubMed] [Google Scholar]
  23. Wilson R. S., Schneider J. A., Beckett L. A., Evans D. A., Bennett D. A. Progression of gait disorder and rigidity and risk of death in older persons. Neurology. 2002 Jun 25;58(12):1815–1819. doi: 10.1212/wnl.58.12.1815. [DOI] [PubMed] [Google Scholar]
  24. Wilson Robert S., Beckett Laurel A., Barnes Lisa L., Schneider Julie A., Bach Julie, Evans Denis A., Bennett David A. Individual differences in rates of change in cognitive abilities of older persons. Psychol Aging. 2002 Jun;17(2):179–193. [PubMed] [Google Scholar]
  25. Wilson Robert S., Mendes De Leon Carlos F., Barnes Lisa L., Schneider Julie A., Bienias Julia L., Evans Denis A., Bennett David A. Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA. 2002 Feb 13;287(6):742–748. doi: 10.1001/jama.287.6.742. [DOI] [PubMed] [Google Scholar]
  26. Wilson Robert S., Schneider Julie A., Barnes Lisa L., Beckett Laurel A., Aggarwal Neelum T., Cochran Elizabeth J., Berry-Kravis Elizabeth, Bach Julie, Fox Jacob H., Evans Denis A. The apolipoprotein E epsilon 4 allele and decline in different cognitive systems during a 6-year period. Arch Neurol. 2002 Jul;59(7):1154–1160. doi: 10.1001/archneur.59.7.1154. [DOI] [PubMed] [Google Scholar]
  27. Yaffe K., Cauley J., Sands L., Browner W. Apolipoprotein E phenotype and cognitive decline in a prospective study of elderly community women. Arch Neurol. 1997 Sep;54(9):1110–1114. doi: 10.1001/archneur.1997.00550210044011. [DOI] [PubMed] [Google Scholar]

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