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

Anastasi, F.; Genius, P.; Rodriguez-Fernandez, B.; Yang, C.; Gorijala, P.; Timsina, J.; Hernandez-Villamizar, F.; Lorenzini, L.; del Campo, M.; Sanchez-Benavides, G.; Minguillon, C.; Navarro, A.; Cruchaga, C.; Suarez-Calvet, M.; Vilor-Tejedor, N.

2024-07-24 genetic and genomic medicine
10.1101/2024.07.23.24310854 medRxiv
Show abstract

Several studies have identified blood proteins that influence brain aging performance in mice, yet translating these findings to humans remains challenging. Here we found that higher predicted plasma levels of Tissue Inhibitor of Metalloproteinases 2 (TIMP2) were significantly associated with improved global cognition and memory performance in humans. We first identified 12 proteins with aging or rejuvenating effects on murine brains through a systematic review. Using protein quantitative trait loci data for these proteins, we computed polygenic scores as proxies for plasma protein levels and validated their prediction accuracy in two independent cohorts. Association models between genetic proxies and cognitive performance highlighted the significance of TIMP2, also when the models were stratified by sex, APOE-{varepsilon}4, and A{beta}42 status. This finding aligns with TIMP2s brain-rejuvenating role in murine models, suggesting it as a promising therapeutic target for brain aging and age-related brain diseases in humans.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.