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APOE genotype predicts when — not whether — one is predisposed to develop Alzheimer disease

Nature Genetics volume 19, pages 321–322 (1998)Cite this article

In an elderly population of 4,932 that included 694 subjects aged 85 and older, we studied the occurrence of Alzheimer disease (AD) in relation to APOE genotype1,2. APOE has three alleles, ε2, ε3 and ε4 — the latter of which has been associated with an increased age-specific risk of AD (ref. 1). We screened all subjects for cognitive dysfunction using either the modified mini-mental state examination3 (3MS) or a structured questionnaire4. A weighted random sample of 878 subjects was then studied with both the dementia questionnaire5 (DQ) and a detailed follow-up clinical assessment6 (CA). We investigated the remaining 4,054 with the DQ and CA when their prior results suggested cognitive impairment. A physician (D.C.S. or J.C.S.B.) reviewed the results and examined most subjects with apparent dementia. Medical records and laboratory studies (including neuroimaging) were sought, and a consensus panel of geropsychiatrists, neurologists and neuropsychologists then made final diagnoses and assigned onset ages, defined as the year subjects unambiguously met DSM-III-R criteria for dementia. Onset ages were believed accurate to within a year in most cases. We found 322 demented individuals, 220 with definite, probable or possible AD (ref. 7). In 25 autopsied cases, 17 of 18 clinical diagnoses of probable or possible AD (94.4%) were confirmed neuropathologically. Four of the five other subjects with AD neuropathology had been categorized clinically as, "dementia, undetermined aetiology," which retains AD in the differential diagnosis.

We identified all subjects who were not demented five years before their last observation and then estimated five-year disease-free survival using the Kaplan Meier product-limit method8. Analyses were limited to the last five years to curtail bias from excess mortality in late dementia. In a separate investigation, we observed an age-standardized mortality ratio of 0.82 (n.s.) in the first five years after AD onset. Details of the analyses and adjustment procedures, and their rationale, are available at http://www.mh.jhsph/survival.

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Figure 1: Disease-free survival by age for four APOE genotypes.
Figure 2: Disease-free survival by age for groups defined by number of APOE ε4 alleles.

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Acknowledgements

We thank the Neurogenetics Laboratory of the Bryan Alzheimer Disease Research Center at Duke University for determining the APOE genotypes from buccal material. J. Anthony and R. Brookmeyer provided helpful discussions on methods. We thank G. Einstein for her helpful critique of the manuscript.

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Authors and Affiliations

  1. Department of Mental Hygiene, The Johns Hopkins University, 624 North Broadway, Baltimore, 21205, Maryland, USA

    Marion R Meyer & John C S Breitner

  2. College of Family Life, Utah State University, Logan, Utah, USA

    JoAnn T Tschanz, Maria C Norton & Bonita W Wyse

  3. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina, USA

    Kathleen A Welsh-Bohmer, David C Steffens & John C S Breitner

  4. The Joseph and Kathleen Bryan Alzheimers Disease Research Center, Duke University, Durham, North Carolina, USA

    Kathleen A Welsh-Bohmer & John C S Breitner

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Meyer, M., Tschanz, J., Norton, M. et al. APOE genotype predicts when — not whether — one is predisposed to develop Alzheimer disease. Nat Genet 19, 321–322 (1998). https://doi.org/10.1038/1206

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