Objective: To investigate the relationship between cognitive reserve (CR) and clinical progression across the Alzheimer’s disease (AD) spectrum. Methods: We selected 839 Aβ-positive subjects with normal cognition (NC, n=175), mild cognitive impairment (MCI, n=437) or AD dementia (n=227) from the Alzheimer’s Disease Neuroimaging Initiative. CR was quantified using standardized residuals (W-scores) from a (covariate-adjusted) linear regression with global cognition (ADAS-Cog 13) as an independent variable-of-interest, and either gray matter volumes or white matter hyperintensity volume as dependent variables. These W-scores, 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]= .22, p<.001) and slower decline in memory (β=.48, p<.001) and executive functions (β=.67, p<.001). Stratified by disease stage, we found similar results for NC (diagnostic conversion: HR=.30, p=.038; ADNI-MEM: β=.52, p=.028; ADNI-EF: β=.42, p=.077) and MCI (diagnostic conversion: HR=.21, p<.001; ADNI-MEM: β=.43, p=.003; ADNI-EF: β=.59, p<.001), but opposite findings (i.e. more rapid decline) for AD dementia (ADNI-MEM: β=-.91, p=.002; ADNI-EF: β=-.77, p=.081). Conclusions: Among Aβ-positive individuals, greater CR related to attenuated clinical progression in pre-dementia stages of AD, but accelerated cognitive decline after the onset of dementia.