Differential effects of cognitive reserve and brain reserve on cognition in Alzheimer disease

To examine cross-sectional effects of cognitive reserve (CR) and brain reserve (BR) on cognition across the spectrum of Alzheimer disease (AD).

We included 663 AD biomarker-positive participants with dementia (probable AD, n = 462) or in the predementia stages (preclinical/prodromal AD, n = 201). Education was used as a proxy of CR and intracranial volume as a proxy of BR. Cognition was assessed across 5 domains (memory, attention, language, visuospatial, and executive functions). We performed multiple linear regression models to examine effects of CR and BR on cognitive domain Z scores, adjusted for cerebral atrophy. Furthermore, we assessed differences in effects according to disease stage and across degrees of total reserve using a 4-level variable (high CR/high BR, high CR/low BR, low CR/high BR, and low CR/low BR).

We found positive, independent effects of both CR and BR across multiple cognitive domains. Stratification for disease stage showed that effects of CR on attention and executive functioning were greater in predementia than in dementia (β = 0.39 vs β = 0.21 [Welch t = 2.40, p < 0.01] and β = 0.46 vs β = 0.26 [t = 2.83, p < 0.01]). Furthermore, we found a linear trend for better cognitive performance in all domains in the high CR/high BR group, followed by high CR/low BR, low CR/high BR, and then low CR/low BR (p for trend <0.05).

CR and BR both independently mitigate cognitive symptoms in AD. The positive effect of CR is most strongly expressed in the predementia stages and the additive effects of high CR and BR are most beneficial.