Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women

Topic: Amyloid, tau and blood-test diagnosis

Late-onset Alzheimer disease (AD) is associated with the apolipoprotein E (APOE)-epsilon4 allele. In late-onset familial AD, women have a significantly higher risk of developing the disease than do men. The aim of this study was to determine whether the gender difference in familial AD is a function of APOE genotype. We studied 58 late-onset familial AD kindreds. Kaplan-Meier survival analysis was used to assess genotype-specific distributions of age at onset. Odds ratios were estimated by logistic regression with adjustment for age and by conditional logistic regression with stratification on families. All methods detected a significant gender difference for the epsilon4 heterozygous genotype. In women, epsilon4 heterozygotes had higher risk than those without epsilon4; there was no significant difference between epsilon4 heterozygotes and epsilon4 homozygotes. In men, epsilon4 heterozygotes had lower risk than epsilon4 homozygotes; there was not significant difference between epsilon4 heterozygotes and those without epsilon4. A direct comparison of epsilon4 heterozygous men and women revealed a significant twofold increased risk in women. We confirmed these results in 15 autopsy-confirmed AD kindreds from the National Cell Repository at Indiana University Alzheimer Disease Center. These observations are consistent with the increased incidence of familial AD in women and may be a critical clue to the role of gender in the pathogenesis of AD.

Key findings

• Late-onset Alzheimer disease (AD) is associated with the apolipoprotein E (APOE)-epsilon4 allele.
• In late-onset familial AD, women have a significantly higher risk of developing the disease than do men.
• All methods detected a significant gender difference for the epsilon4 heterozygous genotype.
• In women, epsilon4 heterozygotes had higher risk than those without epsilon4; there was no significant difference between epsilon4 heterozygotes and epsilon4 homozygotes.
• In men, epsilon4 heterozygotes had lower risk than epsilon4 homozygotes; there was not significant difference between epsilon4 heterozygotes and those without epsilon4.

Why it matters

In families with late-onset Alzheimer's disease, women with one APOE epsilon4 allele had about twice the risk of men with the same genotype. This helps explain why women may be more affected but does not provide a way to treat, cure or prevent the disease.

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Study details

• Participants58
• Evidence strengthLow

Read the original

• PubMed: 8644745
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• Free full text: PubMed Central →

Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).

@article{payami1996-8644745,
  author  = {Payami, H. and Zareparsi, S. and Montee, K. R. and Sexton, G. J. and Kaye, J. A. and Bird, T. D. and Yu, C. E. and Wijsman, E. M. and others},
  title   = {{Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women}},
  journal = {American journal of human genetics},
  year    = {1996},
  pmid    = {8644745}
}

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