Sex-specific early cognitive changes are linked to global and pathway-specific genetic risk for Alzheimer's disease in at-risk individuals

Biology of sex differences

Biol Sex Differ. 2026 Feb 17. doi: 10.1186/s13293-025-00800-w. Online ahead of print.

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative condition in which genetic predisposition plays a key role, yet the sex-specific mechanisms linking genetic risk to early cognitive changes remain unclear. This study examined the impact of polygenic risk scores (PRS) on early cognitive changes in 318 cognitively unimpaired participants from the ALFA+ cohort, a nested longitudinal cohort from the ALFA study (see details in Study Participants Section, Methods). Participants were followed for three years, with assessments across five cognitive domains and a preclinical composite (PACC).