Risk of alzheimer disease is associated with parental age among apolipoprotein E ε4 heterozygotes

L. A. Farrer, L. A. Cupples, W. A. Kukull, L. Volicer, J. M. Wells, A. Kurz, R. C. Green, H. Chui, R. Duara, S. A. Auerbach, E. Larson, N. Lautenschlager, P. A. Wolf, R. D'Agostino, J. Ordovas, E. Schaefer, J. H. Growdon, J. L. Haines

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6 Scopus citations


Recent studies have demonstrated an association between apolipoprotein E (APOE) genotype and the risk of Alzheimer disease (AD). There are also several reports suggesting that parental age is a risk factor for AD. We examined APOE genotypes and parental ages in 583 consecutive cases of probable or definite AD ascertained through eight AD specialty clinics, and 1092 non-demented participants of the Framingham Study who were matched for sex, year of birth and survival age. We found that parents of patients with AD were approximately one year older than parents of controls at the time of birth. This pattern of association was greater among persons having the APOE ε3/ε4 genotype and possibly the APOE ε2/ε3 genotype, but was not evident among subjects with other APOE genotypes, Among APOE ε3/ε4 persons, a 10 year increase in paternal age or maternal age increased the odds of developing AD about 1.6 times. These observations suggest that individuals having both a single copy of ε4 and older parents, have a higher risk for developing AD than persons with only the ε4 risk factor. In contrast, parental age did not appear to influence substantially the risk of AD among ε3 or ε4 homozygotes. There was a trend toward decreased parental age among ε2/ε4 cases compared with ε2/ε4 controls, but a much larger sample of subjects with this genotype is needed to draw firm conclusions. Confounding between maternal and paternal ages did not allow distinction of hypotheses related to male or female reproductive patterns nor diminished the possibility that parental age is a surrogate for an unidentified risk factor. Regardless, the dissimilar patterns of association between parental age and risk of AD across APOE genotype groups suggests that parental age is a modifying rather than a primary risk factor.

Original languageEnglish (US)
Pages (from-to)83-91
Number of pages9
JournalAlzheimer's Research
Issue number3
StatePublished - Jan 1 1997


  • Alzheimer's disease
  • APOE genotype
  • Parental age
  • Risk factor

ASJC Scopus subject areas

  • Neuroscience(all)
  • Neuropsychology and Physiological Psychology


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