Moderating effects of cognitive reserve on the relationship between brain structure and cognitive abilities in middle-aged and older adults.

The cognitive reserve (CR) hypothesis is reinforced by negative moderating effects, suggesting that those with higher CR are less reliant on brain structure for cognitive function. Previous research on CR's moderating effects yielded inconsistent results, motivating our 3 studies using UK Biobank data. Study I examined five CR proxies' moderating effects on global, lobar, and regional brain-cognition models; study II extended study I by using a larger sample size; and study III investigated age-related moderating effects on the hippocampal regions. In study I, most moderating effects were negative and none survived the multiple comparison correction, but study II identified 13 global-level models with significant negative moderating effects that survived correction. Study III showed age influenced CR proxies' moderating effects in hippocampal regions. Our findings suggest that the effects of CR proxies on brain integrity and cognition varied depending on the proxy used, brain integrity indicators, cognitive domain, and age group. This study offers significant insights regarding the importance of CR for brain integrity and cognitive outcomes.