Sex‐specific genetic architecture of late‐life memory performance

• Published in: Alzheimer's & dementia Vol. 20; no. 2; pp. 1250 - 1267
• Main Authors: Eissman, Jaclyn M., Archer, Derek B., Mukherjee, Shubhabrata, Lee, Michael L., Choi, Seo‐Eun, Scollard, Phoebe, Trittschuh, Emily H., Mez, Jesse B., Bush, William S., Kunkle, Brian W., Naj, Adam C., Gifford, Katherine A., Cuccaro, Michael L., Cruchaga, Carlos, Pericak‐Vance, Margaret A., Farrer, Lindsay A., Wang, Li‐San, Schellenberg, Gerard D., Mayeux, Richard P., Haines, Jonathan L., Jefferson, Angela L., Kukull, Walter A., Keene, C. Dirk, Saykin, Andrew J., Thompson, Paul M., Martin, Eden R., Bennett, David A., Barnes, Lisa L., Schneider, Julie A., Crane, Paul K., Hohman, Timothy J., Dumitrescu, Logan
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.02.2024; John Wiley and Sons Inc
• Subjects: Aging; Alzheimer Disease - genetics; Alzheimer's disease; Candidates; Chromosomes; Cognition; Cognitive ability; Cognitive Aging; Dementia; endophenotypes; Female; Gender differences; Genes; Genome-Wide Association Study; Genomics; GWAS; Hispanic Americans; Humans; Male; Memory; Neuropathology; Neuropsychology; Older people; Sex Characteristics; Sex differences; Sexes; sex‐specific; Women; sex-specific; GWAS; memory; cognition; Genomics; aging; endophenotypes; Alzheimer's disease; sex differences
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.13507

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.