A Polygenic Risk Score for Hand Grip Strength is Associated with Cognitive Function in Mid‐to‐Late Life Adults

Background Lower muscular fitness is a risk factor for Alzheimer’s disease (AD). Hand grip strength (HGS) specifically ‐ a proxy for muscular fitness ‐ is a heritable predictor of cognitive decline in aging adults. However, the genetic component of HGS has not yet been explored with respect to cognitive decline. Therefore, we examined the association between a polygenic risk score (PRS) for hand grip strength (HGS) and cognitive function in mid‐to‐late life individuals. Method We accessed data for 22,759 unrelated adults of European ancestry (ages 45‐86) from the Canadian Longitudinal Study on Aging (CLSA), calculating a PRS for HGS using the PRS‐CS‐Auto method and summary statistics from Willems et al., 2017. Linear models were used to test for PRS effects on baseline memory and executive function t‐scores, co‐varying for physical activity and other lifestyle and demographic factors. We also explored interactions with measured hand grip strength, physical activity level, sex, and age. Finally, we tested if our HGS‐PRS was able to significantly augment the predictive performance of a benchmark AD‐PRS, calculated using summary statistics from Bellenguez et al., 2022. Result A higher HGS‐PRS was associated with better global cognitive performance (p = 6.05e‐08). This effect remained significant after controlling for a full set of covariates, including cardiovascular fitness, physical activity, and lean muscle mass (p = 3.14e‐05). Interaction models revealed that age, sex, measured grip strength, and level of physical activity did not change the relationship between HGS‐PRS and cognition. Finally, when assessing whether the HGS‐PRS could augment the predictive performance of an established AD‐PRS, we found significant improvements to models of memory (p = .0035), executive function (p = 7.13e‐06), and global cognition (p = 3.07e‐06). While statistically significant, the additional variance explained in cognition was very small (improvement in R2∼0.1%). Conclusion Genetic predisposition for greater HGS is significantly associated with better cognitive performance in mid‐late life, regardless of sex, fitness, or levels of physical activity. It is therefore possible that direct mind‐muscle connections account for this observation, rather than indirect effects of active lifestyle. Further analyses on longitudinal cognitive outcomes and intermediate brain functional phenotypes are warranted.