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. 2002 Sep;39(9):639–643. doi: 10.1136/jmg.39.9.639

Apolipoprotein E4 is only a weak predictor of dementia and cognitive decline in the general population

A Yip 1, C Brayne 1, D Easton 1, D Rubinsztein 1
PMCID: PMC1735244  PMID: 12205106

Abstract

Background: Apolipoprotein E (APOE) polymorphisms are unequivocally associated with risk for Alzheimer's disease (AD). It is crucial to understand how this genetic factor affects dementia risk in the general population, as well as in narrowly diagnosed, selected, patient groups.

Methods: We assessed the cross sectional association between APOE genotype and dementia status in a community based sample, the MRC Cognitive Function and Ageing Study (MRC CFAS). In addition, we tested the effects of APOE genotypes on the differences in MMSE scores between the first and third assessment waves (about six years apart), an index of cognitive decline.

Results: The APOE ε4 allele conferred increased risk for dementia (OR=1.5, 95% CI=1.1 to 2.2) compared to ε3 in the MRC CFAS sample. Compared with APOE ε3/ε3 subjects, those with the ε3/ε4 genotypes were not at significantly higher risk for dementia (OR=1.1, 95% CI=0.6 to 1.9), although ε4/ε4 subjects were (OR= 3.8, 95% CI=1.0 to 14.0). Risk estimates were not different between men and women. Notably, our risk estimates for dementia were significantly lower than those reported for a diagnosis of Alzheimer's disease. MMSE scores at wave 3 and the difference in MMSE between baseline and at the third assessment wave were not different across APOE genotypes.

Interpretation: The APOE ε4 allele is a weaker predictor for dementia in the general population than for AD. This may be because dementia can be caused by non-AD pathological processes and because most prevalent dementia occurs at an age when the APOE ε4 effect on AD risk (and therefore dementia) has started to decline.

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Selected References

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  1. Asada T., Kariya T., Yamagata Z., Kinoshita T., Asaka A. ApoE epsilon 4 allele and cognitive decline in patients with Alzheimer's disease. Neurology. 1996 Aug;47(2):603–603. doi: 10.1212/wnl.47.2.603. [DOI] [PubMed] [Google Scholar]
  2. Basun H., Grut M., Winblad B., Lannfelt L. Apolipoprotein epsilon 4 allele and disease progression in patients with late-onset Alzheimer's disease. Neurosci Lett. 1995 Jan 2;183(1-2):32–34. doi: 10.1016/0304-3940(94)11107-t. [DOI] [PubMed] [Google Scholar]
  3. Caselli R. J., Graff-Radford N. R., Reiman E. M., Weaver A., Osborne D., Lucas J., Uecker A., Thibodeau S. N. Preclinical memory decline in cognitively normal apolipoprotein E-epsilon4 homozygotes. Neurology. 1999 Jul 13;53(1):201–207. doi: 10.1212/wnl.53.1.201. [DOI] [PubMed] [Google Scholar]
  4. Collighan G., Macdonald A., Herzberg J., Philpot M., Lindesay J. An evaluation of the multidisciplinary approach to psychiatric diagnosis in elderly people. BMJ. 1993 Mar 27;306(6881):821–824. doi: 10.1136/bmj.306.6881.821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Copeland J. R., Dewey M. E., Griffiths-Jones H. M. A computerized psychiatric diagnostic system and case nomenclature for elderly subjects: GMS and AGECAT. Psychol Med. 1986 Feb;16(1):89–99. doi: 10.1017/s0033291700057779. [DOI] [PubMed] [Google Scholar]
  6. Craft S., Teri L., Edland S. D., Kukull W. A., Schellenberg G., McCormick W. C., Bowen J. D., Larson E. B. Accelerated decline in apolipoprotein E-epsilon4 homozygotes with Alzheimer's disease. Neurology. 1998 Jul;51(1):149–153. doi: 10.1212/wnl.51.1.149. [DOI] [PubMed] [Google Scholar]
  7. Dik M. G., Jonker C., Bouter L. M., Geerlings M. I., van Kamp G. J., Deeg D. J. APOE-epsilon4 is associated with memory decline in cognitively impaired elderly. Neurology. 2000 Apr 11;54(7):1492–1497. doi: 10.1212/wnl.54.7.1492. [DOI] [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. Fratiglioni L., Launer L. J., Andersen K., Breteler M. M., Copeland J. R., Dartigues J. F., Lobo A., Martinez-Lage J., Soininen H., Hofman A. Incidence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology. 2000;54(11 Suppl 5):S10–S15. [PubMed] [Google Scholar]
  10. Growdon J. H., Locascio J. J., Corkin S., Gomez-Isla T., Hyman B. T. Apolipoprotein E genotype does not influence rates of cognitive decline in Alzheimer's disease. Neurology. 1996 Aug;47(2):444–448. doi: 10.1212/wnl.47.2.444. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. Hofman A., Ott A., Breteler M. M., Bots M. L., Slooter A. J., van Harskamp F., van Duijn C. N., Van Broeckhoven C., Grobbee D. E. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet. 1997 Jan 18;349(9046):151–154. doi: 10.1016/S0140-6736(96)09328-2. [DOI] [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. Jorm A. F., Jolley D. The incidence of dementia: a meta-analysis. Neurology. 1998 Sep;51(3):728–733. doi: 10.1212/wnl.51.3.728. [DOI] [PubMed] [Google Scholar]
  15. Juva K., Verkkoniemi A., Viramo P., Polvikoski T., Kainulainen K., Kontula K., Sulkava R. APOE epsilon4 does not predict mortality, cognitive decline, or dementia in the oldest old. Neurology. 2000 Jan 25;54(2):412–415. doi: 10.1212/wnl.54.2.412. [DOI] [PubMed] [Google Scholar]
  16. Kurz A., Egensperger R., Haupt M., Lautenschlager N., Romero B., Graeber M. B., Müller U. Apolipoprotein E epsilon 4 allele, cognitive decline, and deterioration of everyday performance in Alzheimer's disease. Neurology. 1996 Aug;47(2):440–443. doi: 10.1212/wnl.47.2.440. [DOI] [PubMed] [Google Scholar]
  17. Lobo A., Launer L. J., Fratiglioni L., Andersen K., Di Carlo A., Breteler M. M., Copeland J. R., Dartigues J. F., Jagger C., Martinez-Lage J. Prevalence of dementia and major subtypes in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology. 2000;54(11 Suppl 5):S4–S9. [PubMed] [Google Scholar]
  18. Murphy G. M., Jr, Taylor J., Kraemer H. C., Yesavage J., Tinklenberg J. R. No association between apolipoprotein E epsilon 4 allele and rate of decline in Alzheimer's disease. Am J Psychiatry. 1997 May;154(5):603–608. doi: 10.1176/ajp.154.5.603. [DOI] [PubMed] [Google Scholar]
  19. Plassman B. L., Breitner J. C. Apolipoprotein E and cognitive decline in Alzheimer's disease. Neurology. 1996 Aug;47(2):317–320. doi: 10.1212/wnl.47.2.317. [DOI] [PubMed] [Google Scholar]
  20. Rubinsztein D. C., Easton D. F. Apolipoprotein E genetic variation and Alzheimer's disease. a meta-analysis. Dement Geriatr Cogn Disord. 1999 May-Jun;10(3):199–209. doi: 10.1159/000017120. [DOI] [PubMed] [Google Scholar]
  21. Small B. J., Graves A. B., McEvoy C. L., Crawford F. C., Mullan M., Mortimer J. A. Is APOE--epsilon4 a risk factor for cognitive impairment in normal aging? Neurology. 2000 Jun 13;54(11):2082–2088. doi: 10.1212/wnl.54.11.2082. [DOI] [PubMed] [Google Scholar]
  22. Small G. W., Chen S. T., Komo S., Ercoli L., Bookheimer S., Miller K., Lavretsky H., Saxena S., Kaplan A., Dorsey D. Memory self-appraisal in middle-aged and older adults with the apolipoprotein E-4 allele. Am J Psychiatry. 1999 Jul;156(7):1035–1038. doi: 10.1176/ajp.156.7.1035. [DOI] [PubMed] [Google Scholar]
  23. Wenham P. R., Price W. H., Blandell G. Apolipoprotein E genotyping by one-stage PCR. Lancet. 1991 May 11;337(8750):1158–1159. doi: 10.1016/0140-6736(91)92823-k. [DOI] [PubMed] [Google Scholar]

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