Sex-specific genetic architecture of late-life memory performance

Jaclyn M. Eissman, Derek B. Archer, Shubhabrata Mukherjee, Michael L. Lee, Seo Eun Choi, Phoebe Scollard, Emily H. Trittschuh, Jesse B. Mez, William S. Bush, Brian W. Kunkle, Adam C. Naj, Katherine A. Gifford, Michael L. Cuccaro, Carlos Cruchaga, Margaret A. Pericak-Vance, Lindsay A. Farrer, Li San Wang, Gerard D. Schellenberg, Richard P. Mayeux, Jonathan L. HainesAngela L. Jefferson, Walter A. Kukull, C. Dirk Keene, Andrew J. Saykin, Paul M. Thompson, Eden R. Martin, David A. Bennett, Lisa L. Barnes, Julie A. Schneider, Paul K. Crane, Timothy J. Hohman, Logan Dumitrescu

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear. METHODS: We conducted the largest sex-aware genetic study on late-life memory to date (Nmales = 11,942; Nfemales = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants. RESULTS: We identified three sex-specific loci (rs67099044—CBLN2, rs719070—SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633—EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits. DISCUSSION: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory. Highlights: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits.

Original languageEnglish
Pages (from-to)1250-1267
Number of pages18
JournalAlzheimer's and Dementia
Issue number2
StatePublished - Feb 2024


  • Alzheimer's disease
  • GWAS
  • Genomics
  • aging
  • cognition
  • endophenotypes
  • memory
  • sex differences
  • sex-specific


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