Onset ages of cerebrovascular disease and amyloid and effects on cognition in risk-enriched cohorts

The temporal relationship between cerebrovascular disease (V), indicated by white matter hyperintensities, and beta-amyloid (A) in Alzheimer's disease remains unclear, prompting speculation about their potential interdependence. Longitudinal data were employed to estimate onset ages and corresponding disease chronicity for A and V (where disease chronicity is calculated as age at measurement minus estimated age of biomarker abnormality onset). In a large, predominantly cognitively unimpaired dataset (n = 877, ages 43-93 years), a V+ threshold was identified, and Sampled Iterative Local Approximation (SILA) was utilized to illustrate the predictable accumulation trajectory of V post-onset. Investigating the temporal association between A and V onset ages and accumulation trajectories in preclinical years, four operationalizations of time were examined across two initially cognitively unimpaired samples (n = 240 primary sample from Wisconsin Registry for Alzheimer's Prevention; n = 123 replication sample from Wisconsin Alzheimer's Disease Research Center): (i) chronological age, (ii) estimated V+ chronicity, (iii) years since baseline scan, and (iv) estimated A+ chronicity. Results indicated that while both diseases are age-related, their onsets and trajectories are independent of each other. In addition, results indicated that V and A accumulation trajectories were highly predictable relative to onset of positivity for each biomarker. Cognitive decline across multiple cognitive domains was fastest when both V and A were present based on last available amyloid PET and MRI scan, with greater A chronicity being a more salient predictor of cognitive decline in these samples.