Background and Objectives: Evidence on the association of the cognitive reserve (CR) with the cognitive trajectories is limited. We aimed to examine the influence of CR indicator on domain-specific cognitive trajectories taking brain pathologies into account.

Methods: Within the Rush Memory and Aging Project, 1,697 dementia-free participants (mean age: 79.6 years) were followed up to 21 years. CR indicator encompassing education, early-life, mid-life, and late-life cognitive activities, and late-life social activity was ascertained at baseline and categorized as tertiles (the lowest, middle, and highest). Global cognition, episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed were assessed annually with 19 tests, from which composite scores were derived. During the follow-up, 648 died and underwent autopsies to evaluate brain pathologies. Data were analyzed using linear mixed-effect models.

Results: Among the participants, the score of the CR indicator ranged from -8.00 to 5.74 (mean: 0.00±2.23). In multi-adjusted mixed-effect models, compared to the lowest CR, the highest was related to a slower decline in global cognition (β=0.028, 95% confidence interval [CI]: 0.012 to 0.043), episodic memory (β=0.028, 95% CI: 0.010 to 0.047) and working memory (β=0.019, 95% CI: 0.005 to 0.033) during the follow-up. In brain pathological data analysis, the association of the highest CR with cognitive function changes remained significant among participants with high Alzheimer's disease pathology or gross infarcts.

Discussion: High CR indicator is associated with preserved global cognitive function, episodic memory, and working memory, even in the presence of brain pathologies. Our findings highlight the important role of high CR accumulation in the prevention of cognitive decline.