Association of Lifespan Cognitive Reserve Indicator With Dementia Risk in the Presence of Brain Pathologies.

Importance: Evidence on the association of lifespan cognitive reserve (CR) with dementia is limited, and the strength of this association in the presence of brain pathologies is unknown.

Objective: To examine the association of lifespan CR with dementia risk, taking brain pathologies into account.

Design, Setting, and Participants: This study used data from 2022 participants in the Rush Memory and Aging Project, an ongoing community-based cohort study with annual follow-up from 1997 to 2018 (mean follow-up, 6 years; maximum follow-up, 20 years). After excluding 420 individuals who had prevalent dementia, missing data on CR, or dropped out, 1602 dementia-free adults were identified at baseline and evaluated to detect incident dementia. During follow-up, 611 died and underwent autopsies. Data were analyzed from May to September 2018.

Exposures: Information on CR factors (education; early-life, midlife, and late-life cognitive activities; and social activities in late life) was obtained at baseline. Based on these factors, lifespan CR scores were captured using a latent variable from a structural equation model and was divided into tertiles (lowest, middle, and highest).

Main Outcomes and Measures: Dementia was diagnosed following international criteria. Neuropathologic evaluations for Alzheimer disease and other brain pathologies were performed in autopsied participants. The association of lifespan CR with dementia or brain pathologies was estimated using Cox regression models or logistic regression.

Results: Of the 1602 included participants, 1216 (75.9%) were women, and the mean (SD) age was 79.6 (7.5) years. During follow-up, 386 participants developed dementia (24.1%), including 357 participants with Alzheimer disease-related dementia (22.3%). The multiadjusted hazards ratios (HRs) of dementia were 0.77 (95% CI, 0.59-0.99) for participants in the middle CR score tertile and 0.61 (95% CI, 0.47-0.81) for those in the highest CR score tertile compared with those in the lowest CR score tertile. In autopsied participants, CR was not associated with most brain pathologies, and the association of CR with dementia remained significant after additional adjustment for brain pathologies (HR, 0.60; 95% CI, 0.42-0.86). The highest CR score tertile was associated with a reduction in dementia risk, even among participants with high Alzheimer disease pathology (HR, 0.57; 95% CI, 0.37-0.87) and any gross infarcts (HR, 0.34; 95% CI, 0.18-0.62).

Conclusions and Relevance: High lifespan CR is associated with a reduction in dementia risk, even in the presence of high brain pathologies. Our findings highlight the importance of lifespan CR accumulation in dementia prevention.