Cognitive reserve and clinical progression in Alzheimer disease A paradoxical relationship

Objective To investigate the relationship between cognitive reserve (CR) and clinical progression across the Alzheimer disease (AD) spectrum. Methods We selected 839 beta-amyloid (A beta)-positive participants with normal cognition (NC, n = 175), mild cognitive impairment (MCI, n = 437), or AD dementia (n = 227) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). CR was quantified using standardized residuals (W scores) from a (covariate-adjusted) linear regression with global cognition (13-item Alzheimer's Disease Assessment Scale-cognitive subscale) as an independent variable of interest, and either gray matter volumes or white matter hyperintensity volume as dependent variables. TheseWscores, reflecting whether an individual's degree of cerebral damage is lower or higher than clinically expected, were tested as predictors of diagnostic conversion (i. e., NC to MCI/ AD dementia, or MCI to AD dementia) and longitudinal changes in memory (ADNI-MEM) and executive functions (ADNI-EF). Results The median follow-up period was 24 months (interquartile range 6-42). Corrected for age, sex, APOE4 status, and baseline cerebral damage, higher gray matter volume-based W scores (i. e., greater CR) were associated with a lower diagnostic conversion risk (hazard ratio [ HR] 0.22, p < 0.001) and slower decline in memory (beta = 0.48, p < 0.001) and executive function (beta = 0.67, p < 0.001). Stratified by disease stage, we found similar results for NC (diagnostic conversion: HR 0.30, p = 0.038; ADNI-MEM: beta = 0.52, p = 0.028; ADNI-EF: beta = 0.42, p = 0.077) and MCI (diagnostic conversion: HR 0.21, p < 0.001; ADNI-MEM: beta = 0.43, p = 0.003; ADNI-EF: beta = 0.59, p < 0.001), but opposite findings (i. e., more rapid decline) for AD dementia (ADNI-MEM: beta =-0.91, p = 0.002; ADNI-EF: beta = -0.77, p = 0.081). Conclusions Among A beta-positive individuals, greater CR related to attenuated clinical progression in predementia stages of AD, but accelerated cognitive decline after the onset of dementia.