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

Jaclyn M. Eissman; Alexandra N. Regelson; Skylar Walters; Derek B. Archer; Alaina Durant; Shubhabrata Mukherjee; Michael L. Lee; Seo‐Eun Choi; Phoebe Scollard; Emily H. Trittschuh; Jesse B Mez; Moon-Il Kang; William S. Bush; Brian W. Kunkle; Adam Christian Naj; Katherine A. Gifford; Murat Bilgel; Amanda B. Kuzma; The Alzheimer’s Disease Neuroimaging Initiative (ADNI); The Alzheimer’s Disease Sequencing Project (ADSP); Michael L. Cuccaro; Carlos Cruchaga; Margaret Ann Pericak‐Vance; Lindsay A. Farrer; Li-San Wang; Gerard D. Schellenberg; Badri Narayan Vardarajan; Richard P Mayeux; Jonathan L. Haines; Angela Lee Jefferson

doi:10.1101/2025.05.26.25328369

Genetic & Genomic MedicinemedRxivMay 26, 2025

Preprint

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

Jaclyn M. Eissman iD, Alexandra N. Regelson, Skylar Walters, Derek B. Archer iD, Alaina Durant, Shubhabrata Mukherjee iD, Michael L. Lee iD, Seo‐Eun Choi iD, Phoebe Scollard iD, Emily H. Trittschuh iD, Jesse B Mez iD, Moon-Il Kang iD, William S. Bush iD, Brian W. Kunkle iD, Adam Christian Naj iD, Katherine A. Gifford iD, Murat Bilgel iD, Amanda B. Kuzma iD, The Alzheimer’s Disease Neuroimaging Initiative (ADNI), The Alzheimer’s Disease Sequencing Project (ADSP), Michael L. Cuccaro iD, Carlos Cruchaga iD, Margaret Ann Pericak‐Vance iD, Lindsay A. Farrer iD, Li-San Wang, , Logan C. Dumitrescu iD

Abstract

We previously identified sex-specific genetic loci associated with memory performance, a strong Alzheimers 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.

PDF DOI