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

Abstract

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.

Figure 1. Selection procedure of the sample

Aβ = β-amyloid; AD = Alzheimer disease; ADNI = Alzheimer's Disease Neuroimaging Initiative; MCI = mild cognitive impairment; NC = normal cognition; NPA = neuropsychological assessment.

Figure 2. Trajectories of memory and executive functions by level of cognitive reserve

The Y-axis represents estimated marginal means. Cognitive reserve groups were created (for visualization purposes) by calculating tertiles in each disease stage—(A) normal cognition, (B) mild cognitive impairment, and (C) Alzheimer disease (AD) dementia—based on mean gray matter (GM)–based W scores in the temporoparietal mask. The lines displayed correspond to APOE4-positive men with a (disease stage–specific) average age and intracranial volume–adjusted GM volume in the temporoparietal cortex. In the linear mixed models, W scores were included as a continuous variable, and memory and executive functions composite scores were multiplied by 100. Note that the maximum follow-up time for AD dementia participants is shorter (i.e., 24 months) compared to the other 2 groups (i.e., 120 months). ADNI = Alzheimer's Disease Neuroimaging Initiative; ADNI-EF = standardized composite score based on a clock drawing task, animal and vegetable category fluency, the Trail-making task, Digit Span Backwards from the Wechsler Memory Scale–Revised, and the digit–symbol substitution task from the Wechsler Adult Intelligence Test–Revised; ADNI-MEM = standardized composite score based on the Alzheimer’s Disease Assessment Scale–cognitive subscale word list learning task, the Rey Auditory Verbal Learning Test, Logical Memory from the Wechsler Memory Scale–Revised, and the Mini-Mental State Examination recall task.