Abstract / Summary
Educational attainment is a widely used proxy of cognitive reserve (CR), but it remains unclear whether its association with cognition persists after accounting for multiple forms of brain pathology. It is also uncertain whether CR-related associations are more evident for baseline cognitive performance or for longitudinal cognitive change. This study examined education and a multidimensional CR questionnaire in relation to cognition and multimodal pathology across two aging cohorts representing complementary stages of the Alzheimer’s disease continuum. Data from PREVENT-AD and CIMA-Q were analyzed using cross-sectional and longitudinal models. PREVENT-AD included cognitively unimpaired individuals at increased risk for sporadic Alzheimer’s disease, whereas CIMA-Q included participants spanning cognitively normal status, subjective cognitive decline, mild cognitive impairment, and mild Alzheimer’s disease. Models examined associations between education and cognitive outcomes before and after adjustment for multimodal pathology, including MRI-based white matter hyperintensity volume, deformation-based morphometry measures of neurodegeneration, and plasma Alzheimer’s disease biomarkers. Education was examined in both cohorts, and a multidimensional CR questionnaire was examined in CIMA-Q. Higher education was associated with better cognitive performance across cohorts, and these associations generally persisted after adjustment for cerebrovascular, neurodegenerative, and Alzheimer’s disease-related pathology markers. In CIMA-Q, the CR composite score showed less consistent associations with cognition than education, and exploratory non-education CR subdomains showed small, non-significant associations. Education showed limited and inconsistent associations with measured brain pathology, suggesting that education-cognition associations were not primarily explained by lower pathology burden. Exploratory moderation analyses did not identify significant interactions between CR proxies and pathology markers. Longitudinally, education was more consistently associated with baseline cognitive level than with cognitive change. Education-related trajectory differences were observed mainly for TMT Part B performance in PREVENT-AD, whereas longitudinal associations were less consistent in CIMA-Q. Education was the most consistent proxy associated with better cognitive performance after adjustment for multimodal brain pathology, although it did not significantly moderate the associations between pathology and cognition.