Sex-Specific Genetic Drivers of Memory, Executive Functioning, and Language Performance in Older Adults

dc.contributor.authorEissman, Jaclyn M.
dc.contributor.authorRegelson, Alexandra N.
dc.contributor.authorWalters, Skylar
dc.contributor.authorArcher, Derek B.
dc.contributor.authorDurant, Alaina
dc.contributor.authorMukherjee, Shubhabrata
dc.contributor.authorLee, Michael L.
dc.contributor.authorChoi, Seo-Eun
dc.contributor.authorScollard, Phoebe
dc.contributor.authorTrittschuh, Emily H.
dc.contributor.authorMez, Jesse
dc.contributor.authorKang, Moonil
dc.contributor.authorBush, William S.
dc.contributor.authorKunkle, Brian W.
dc.contributor.authorNaj, Adam C.
dc.contributor.authorGifford, Katherine A.
dc.contributor.authorBilgel, Murat
dc.contributor.authorKuzma, Amanda B.
dc.contributor.authorAlzheimer’s Disease Neuroimaging Initiative (ADNI)
dc.contributor.authorAlzheimer’s Disease Genetics Consortium (ADGC)
dc.contributor.authorAlzheimer’s Disease Sequencing Project (ADSP)
dc.contributor.authorCuccaro, Michael L.
dc.contributor.authorCruchaga, Carlos
dc.contributor.authorPericak-Vance, Margaret A.
dc.contributor.authorFarrer, Lindsay A.
dc.contributor.authorWang, Li-San
dc.contributor.authorSchellenberg, Gerard D.
dc.contributor.authorVardarajan, Badri N.
dc.contributor.authorMayeux, Richard
dc.contributor.authorHaines, Jonathan L.
dc.contributor.authorJefferson, Angela L.
dc.contributor.authorKukull, Walter A.
dc.contributor.authorKeene, C. Dirk
dc.contributor.authorSaykin, Andrew J.
dc.contributor.authorThompson, Paul M.
dc.contributor.authorMartin, Eden R.
dc.contributor.authorAlbert, Marilyn S.
dc.contributor.authorJohnson, Sterling C.
dc.contributor.authorEngelman, Corinne D.
dc.contributor.authorFerrucci, Luigi
dc.contributor.authorBennett, David A.
dc.contributor.authorBarnes, Lisa L.
dc.contributor.authorSchneider, Julie A.
dc.contributor.authorResnick, Susan M.
dc.contributor.authorSperling, Reisa A.
dc.contributor.authorCrane, Paul K.
dc.contributor.authorHohman, Timothy J.
dc.contributor.authorDumitrescu, Logan
dc.contributor.departmentRadiology and Imaging Sciences, School of Medicine
dc.date.accessioned2025-07-14T15:12:19Z
dc.date.available2025-07-14T15:12:19Z
dc.date.issued2025-06-02
dc.description.abstractWe previously identified sex-specific genetic loci associated with memory performance, a strong Alzheimer's disease (AD) endophenotype. Here, we expand on this work by conducting sex-specific, cross-ancestral, genome-wide meta-analyses of three cognitive domains (memory, executive functioning, and language) in 33,918 older adults (57% female; 41% cognitively impaired; mean age=73 years) from 10 aging and AD cohorts. All three domains were comparably heritable across sexes. Genome-wide meta-analyses identified three novel loci: a female-specific language decline-associated locus, VRK2 (rs13387871), which is a published candidate for neuropsychiatric traits involving language ability; a male-specific memory decline-associated locus among cognitive impaired, DCHS2 (rs12501200), which is a published candidate gene for AD age-at-onset; and a sex-interaction with baseline executive functioning, AGA (rs1380012), among cognitive impaired. We additionally provide evidence for shared genetic architecture between lifetime estrogen exposure and AD-related cognitive decline. Overall, we identified sex-specific variants, genes, and pathways relating to three cognitive domains among older adults.
dc.eprint.versionPreprint
dc.identifier.citationEissman JM, Regelson AN, Walters S, et al. Sex-Specific Genetic Drivers of Memory, Executive Functioning, and Language Performance in Older Adults. Preprint. medRxiv. 2025;2025.05.26.25328369. Published 2025 Jun 2. doi:10.1101/2025.05.26.25328369
dc.identifier.urihttps://hdl.handle.net/1805/49429
dc.language.isoen_US
dc.publishermedRxiv
dc.relation.isversionof10.1101/2025.05.26.25328369
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourcePMC
dc.subjectSex-specific genetic loci
dc.subjectMemory performance
dc.subjectAlzheimer's disease (AD) endophenotype
dc.titleSex-Specific Genetic Drivers of Memory, Executive Functioning, and Language Performance in Older Adults
dc.typeArticle
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