Similar Genetic Architecture of Alzheimer’s Disease and Differential APOE Effect Between Sexes

Hao Wang, Min Tzu Lo, Sara Brin Rosenthal, Carolina Makowski, Ole A. Andreassen, Rany M. Salem, Linda K. McEvoy, Mark Fiecas, Chi Hua Chen

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Sex differences have been observed in the clinical manifestations of Alzheimer’s disease (AD) and elucidating their genetic basis is an active research topic. Based on autosomal genotype data of 7,216 men and 10,680 women, including 8,136 AD cases and 9,760 controls, we explored sex-related genetic heterogeneity in AD by investigating SNP heritability, genetic correlation, as well as SNP- and gene-based genome-wide analyses. We found similar SNP heritability (men: 19.5%; women: 21.5%) and high genetic correlation (Rg = 0.96) between the sexes. The heritability of APOE ε4-related risks for AD, after accounting for effects of all SNPs excluding chromosome 19, was nominally, but not significantly, higher in women (10.6%) than men (9.7%). In age-stratified analyses, ε3/ε4 was associated with a higher risk of AD among women than men aged 65–75 years, but not in the full sample. Apart from APOE, no new significant locus was identified in sex-stratified gene-based analyses. Our result of the high genetic correlation indicates overall similar genetic architecture of AD in both sexes at the genome-wide averaged level. Our study suggests that clinically observed sex differences may arise from sex-specific variants with small effects or more complicated mechanisms involving epigenetic alterations, sex chromosomes, or gene-environment interactions.

Original languageEnglish (US)
Article number674318
JournalFrontiers in Aging Neuroscience
StatePublished - May 28 2021

Bibliographical note

Funding Information:
This study was supported by National Institutes of Health R56AG061163, R01MH118281; The Alzheimer’s Disease Genetics Consortium (ADGC) were supported by a grant from the National Institute on Aging/National Institutes of Health UO1AG032984 and complete acknowledgments for ADGC are detailed in the ADGC website

Publisher Copyright:
© Copyright © 2021 Wang, Lo, Rosenthal, Makowski, Andreassen, Salem, McEvoy, Fiecas and Chen.


  • Alzheimer’s disease
  • genetic heterogeneity
  • genome-wide association study
  • heritability
  • sex difference


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