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

To examine the association between genetic predisposition to accelerated brain aging-measured with polygenic risk scores (PRS) derived from BrainAge models-and plasma biomarkers of Alzheimer's disease (AD), with attention to age and sex-specific effects.

We 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.

BrainAge PRS moderated the association between age and pTau₂₁₇ levels (β=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.

Genetic 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.