Genetic Predisposition to Hand Grip Strength Predicts Cognitive Decline

Hand grip strength (HGS) is a predictor of cognitive decline in aging. To understand the direct and indirect mechanisms underlying this association, we performed integrative analyses of genetic, cognitive, and autopsy data. A polygenic risk score for HGS (PRS HGS ) was calculated in two independent studies of aging (total n=25,210). Cross-sectional and longitudinal modeling, including mediation with physical activity, assessed the effects of PRS HGS on cognitive performance and postmortem neuropathology. In both cohorts, higher PRS HGS predicted better global cognitive performance ( p = 7.77x10 -4 and 0.025) and improved the predictive performance of an Alzheimer’s disease PRS ( p = 2.5x10 -5 ; p = 0.007). PRS HGS was not associated with any postmortem neuropathology. PRS HGS effects on cognition were only partially and inconsistently mediated by physical activity. Genetic predisposition for greater HGS predicts better cognitive performance in late life, independent from Alzheimer’s disease-related neuropathology. • PRS HGS is significantly associated with better cognitive performance in mid-late life • PRS HGS effects on cognition were not fully mediated by physical activity. • Adding PRS HGS improved existing PRS AD models of cognitive performance. • PRS HGS was not associated with any measured postmortem neuropathology