Proteomic polygenic risk scores of age-related plasma protein levels reveal a role for Metalloproteinase inhibitor 2 (TIMP2) in cognitive performance

Several studies in mice have identified blood proteins that influence brain aging, yet translating these findings into humans remains challenging. To address this gap, we conducted a systematic review that identified 12 proteins reported to have an aging or rejuvenating effect in murine brains. Using protein quantitative trait loci data, we computed proteomic polygenic risk scores (protPRSs) capturing the lifelong genetic predisposition to higher or lower plasma protein levels and their regulation. We first validated the prediction accuracy of these protPRSs in two independent cohorts: 10 protPRSs in the Knight-ADRC and 7 protPRSs in the ALFA+ cohort significantly predicted their corresponding protein levels, although effect sizes were modest. We then examined their association with cognitive performance in cognitively unimpaired individuals at risk of Alzheimer's disease of the ALFA+ cohort. Among the protPRSs tested, the metalloproteinase inhibitor 2 (TIMP2) protPRS was significantly associated with better global cognition and episodic memory. These associations were consistent across stratifications by sex, APOE-ε4, and amyloid-β status, although some did not survive multiple testing corrections. TIMP2 protPRS correlated with measured TIMP2 levels, but actual plasma concentrations were not significantly related to cognition. This finding aligns with murine evidence of TIMP2's brain-rejuvenating role. By leveraging genetic predisposition to protein abundance and regulation, protPRSs may provide complementary insight into long-term biological processes not captured by single protein measurements. Our results support TIMP2 as a candidate for further investigation in the context of brain aging and cognitive decline.