Exploring the neural mechanisms linking healthy aging and cognitive maintenance: insights from Mendelian randomization and mediation analyses

Abstract As global population ages, maintaining cognitive health in elderly is crucial. Previous studies suggest a positive link between healthy aging and cognition, but the neural mechanisms remain unclear. This study used genome-wide association studydata to investigate neural mechanisms between healthy aging and cognition. We employed 2-sample Mendelian randomization to evaluate causal relationship between healthy aging (indexed by a multivariate genetic predictor, mvAge) and 6 cognitive measurements. We then used a 2-step Mendelian randomization approach and mediation analysis to identify brain imaging-derived phenotypes potentially mediating this relationship. Mendelian randomization analysis indicated that healthy aging had a positive causal relationship with various cognitive functions (common executive function, intelligence, cognitive performance, and fluid intelligence score). Two-step Mendelian randomization analysis identified 27 brain imaging-derived phenotypes having robust causal relationships with healthy aging and various cognitive measurements. Mediation analysis suggested that volume of subcallosal cortex might mediate effects of healthy aging on all 4 cognitive functions. Volume of cerebellum’s VIIb could mediate effects on common executive functions, while fractional anisotropy in the anterior thalamic radiation might mediate effects on intelligence and cognitive performance. These findings suggest that specific brain regions may play a potential mediating role in the relationship between healthy aging and cognitive maintenance.