Are the factors associated with cognitive performance generalizable across cohorts?

To examine whether vascular risk and brain atrophy account for cohort differences in the associations between tau burden and cognition across cognitive domains in U.S. POINTER and ADNI.

We analyzed baseline data from 775 U.S. POINTER and 405 ADNI participants without significant cognitive impairment and matched on age, sex, clinical status, and APOE ε4 status. Cognitive outcomes included global cognition, verbal memory, and executive function. Regional tau (entorhinal and meta-temporal), vascular risk biomarkers, and structural MRI measures (entorhinal cortical thickness and hippocampal volume) were examined using linear regression models stratified by amyloid status and adjusted for age, sex, education, and average number of prior cognitive test exposures. Interaction terms (biomarker × cohort) were used to assess cohort differences. False discovery rate (FDR) correction was applied.

Greater tau burden was associated with poorer cognitive performance across global cognition, verbal memory, and executive function in ADNI compared to U.S. POINTER, particularly among Aβ + individuals (corrected p < .05). Unexpectedly, vascular risk biomarkers contributed minimally to cognitive variability in either cohort. Finally, brain atrophy, particularly hippocampal volume, made a tau-independent contribution to verbal memory in ADNI but not in U.S. POINTER, especially among Aβ + individuals (corrected p < .05).

Tau pathology in the presence of Aβ was a stronger predictor of cognition in ADNI than in U.S. POINTER, and this discrepancy was not explained by increased vascular risk or brain atrophy in U.S. POINTER. The drivers of cognition differed between cohorts in a way that is not easily attributable to clinical characteristics.