Polygenic proxies of age-related plasma protein levels reveal TIMP2 role in cognitive performance

Background While numerous studies have identified blood proteins that modulate brain aging in mice, the direct translation of these findings to human health remains a substantial challenge. Bridging this gap is critical for developing interventions that can effectively target human brain aging and associated diseases. Methods We first identified 12 proteins with aging or rejuvenating properties in murine brains through a systematic review. Using protein quantitative trait loci data for these proteins, we developed polygenic scores to predict plasma protein levels, which we then validated in two independent human cohorts. We employed association models to explore the association between these genetically predicted protein levels and cognitive performance, focusing specifically on their interaction with key genetic markers such as sex, APOE -ε4 and Aβ42 status. Results Predicted plasma levels of Tissue Inhibitor of Metalloproteinases 2 (TIMP2) were significantly associated with improved global cognition and memory performance in humans, also when the models were stratified by sex, APOE -ε4, and Aβ42 status. Conclusions This finding aligns with TIMP2's brain-rejuvenating role in murine models, suggesting it as a promising therapeutic target for brain aging and age-related brain diseases in humans.