Cognitive reserve and clinical progression in Alzheimer disease: A paradoxical relationship

Anna Catharina van Loenhoud, Wiesje Maria van der Flier, Alle Meije Wink, Ellen Dicks, Colin Groot, Jos Twisk, Frederik Barkhof, Philip Scheltens, Rik Ossenkoppele, Alzheimer's Disease Neuroimaging Initiative

Research output: Contribution to journalArticleAcademicpeer-review


OBJECTIVE: To investigate the relationship between cognitive reserve (CR) and clinical progression across the Alzheimer disease (AD) spectrum.

METHODS: We selected 839 β-amyloid (Aβ)-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. 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] 0.22, p < 0.001) and slower decline in memory (β = 0.48, p < 0.001) and executive function (β = 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: β = 0.52, p = 0.028; ADNI-EF: β = 0.42, p = 0.077) and MCI (diagnostic conversion: HR 0.21, p < 0.001; ADNI-MEM: β = 0.43, p = 0.003; ADNI-EF: β = 0.59, p < 0.001), but opposite findings (i.e., more rapid decline) for AD dementia (ADNI-MEM: β = -0.91, p = 0.002; ADNI-EF: β = -0.77, p = 0.081).

CONCLUSIONS: Among Aβ-positive individuals, greater CR related to attenuated clinical progression in predementia stages of AD, but accelerated cognitive decline after the onset of dementia.

Original languageEnglish
Pages (from-to)e334-e346
Issue number4
Early online date2 Jul 2019
Publication statusPublished - 23 Jul 2019

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