Contribution of Alzheimer's disease pathology to biological and clinical progression: A longitudinal study across two cohorts

Abstract INTRODUCTION Amyloid beta (Aβ) deposition, tau accumulation, and brain atrophy occurr in sequence, but the contribution of Alzheimer's disease (AD) pathology to biological and clinical progression remains unclear. METHODS We included 290 and 70 participants with longitudinal assessment on Aβ‐positron emission tomography (PET), tau‐PET, magnetic resonance imaging, and cognitive function from the Harvard Aging Brain Study (HABS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) datasets, respectively. Partial least squares structural equation modeling (PLS‐SEM) was used to determine the contribution of AD pathology to the biological and clinical longitudinal changes. RESULTS Imaging biomarkers and cognitive function were significantly associated in cross‐sectional and longitudinal analyses. At the final time point, the percentage of variance explained by PLS‐SEM was 27% for Aβ, 30% for tau (Aβ accounted for 61%), 29% for brain atrophy (tau accounted for 37%), and 37% for cognitive decline (brain atrophy accounted for 35%). DISCUSSION This study highlights distinctive contributing proportions of AD pathology to biological and clinical progression. Treatments targeting Aβ and tau may partially block AD progression.