Relationship between BrainAge Polygenetic Risk Score and plasma biomarkers in the A4/LEARN studies

Background and ObjectivesTo examine the association between genetic predisposition to accelerated brain aging--measured with polygenic risk scores (PRS) derived from BrainAge models--and plasma biomarkers of Alzheimers disease (AD), with attention to age and sex-specific effects. MethodsWe analyzed 1994 cognitively unimpaired participants from the A4/LEARN studies (71.5{+/-}4.8 years; 41% male). We computed the genetic risk of accelerated grey matter loss associated with age using GWAS data from previous studies. Baseline plasma biomarkers included pTau217 (N=980; Eli Lilly immunoassay), and GFAP and NfL (N=1636; Roche Elecsys immunoassay). General linear models tested associations between each PRS and each biomarker, including PRS-by-age interaction terms. Analyses were additionally stratified by sex. ResultsBrainAge PRS moderated the association between age and pTau217 levels ({beta}=0.08{+/-}0.03, p=0.0086), such that higher PRS for BrainAge was associated with increased pTau217 at older ages. Results were robust to covariates. This association was significant in females but not in males. No significant associations were found with GFAP or NfL. DiscussionGenetic risk for accelerated grey matter loss with aging is associated with elevated pTau217 levels in cognitively unimpaired older females. These findings suggest a sex- and age-specific genetic link between brain aging and early AD pathology.