Eissman, Jaclyn M.Archer, Derek B.Mukherjee, ShubhabrataLee, Michael L.Choi, Seo-EunScollard, PhoebeTrittschuh, Emily H.Mez, Jesse B.Bush, William S.Kunkle, Brian W.Naj, Adam C.Gifford, Katherine A.Alzheimer's Disease Neuroimaging Initiative (ADNI)Alzheimer's Disease Genetics Consortium (ADGC)The Alzheimer's Disease Sequencing Project (ADSP)Cuccaro, Michael L.Cruchaga, CarlosPericak-Vance, Margaret A.Farrer, Lindsay A.Wang, Li-SanSchellenberg, Gerard D.Mayeux, Richard P.Haines, Jonathan L.Jefferson, Angela L.Kukull, Walter A.Keene, C. DirkSaykin, Andrew J.Thompson, Paul M.Martin, Eden R.Bennett, David A.Barnes, Lisa L.Schneider, Julie A.Crane, Paul K.Hohman, Timothy J.Dumitrescu, Logan2024-06-272024-06-272024Eissman JM, Archer DB, Mukherjee S, et al. Sex-specific genetic architecture of late-life memory performance. Alzheimers Dement. 2024;20(2):1250-1267. doi:10.1002/alz.13507https://hdl.handle.net/1805/41942Background: 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.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalAlzheimer's diseaseGWASGenomicsAgingCognitionEndophenotypesMemorySex differencesSex-specificArticle