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

Abstract

We 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.

Description
item.page.description.tableofcontents
item.page.relation.haspart
Cite As
Eissman 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
ISSN
Publisher
Series/Report
Sponsorship
Major
Extent
Identifier
Relation
Journal
Source
PMC
Alternative Title
Type
Article
Number
Volume
Conference Dates
Conference Host
Conference Location
Conference Name
Conference Panel
Conference Secretariat Location
Version
Preprint
Full Text Available at
This item is under embargo {{howLong}}