Genetically supported targets and drug repurposing for brain aging: A systematic study in the UK Biobank

Brain age gap (BAG), the deviation between estimated brain age and chronological age, is a promising marker of brain health. However, the genetic architecture and reliable targets for brain aging remains poorly understood. In this study, we estimate magnetic resonance imaging (MRI)-based brain age using deep learning models trained on the UK Biobank and validated with three external datasets. A genome-wide association study for BAG identified two unreported loci and seven previously reported loci. By integrating Mendelian Randomization (MR) and colocalization analysis on eQTL and pQTL data, we prioritized seven genetically supported druggable genes, including MAPT, TNFSF12, GZMB, SIRPB1, GNLY, NMB, and C1RL, as promising targets for brain aging. We rediscovered 13 potential drugs with evidence from clinical trials of aging and prioritized several drugs with strong genetic support. Our study provides insights into the genetic basis of brain aging, potentially facilitating drug development for brain aging to extend the health span.