Cognitive Trajectories from Preclinical Alzheimer's Disease to Dementia

Alzheimer's disease (AD) is marked by progressive cognitive decline, highlighting the importance of cognitive assessment in both clinical practice and research. This study investigates the temporal dynamics of cognitive decline and the differential sensitivity of cognitive measures across the AD spectrum. Cognitive measures, functional assessments, and amyloid-beta (Aβ) and tau positron emission tomography (PET) scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) are analyzed using a latent-time disease progression model. Data from 1,447 participants across cognitively normal, mild cognitive impairment, and dementia stages are positioned along an estimated AD timeline. The model estimates a ∼20-year progression from initial Aβ PET positivity to late-stage dementia. Cognitive trajectories reveal that cognitive measures deviate at different time points, with varying levels of abnormality across the disease continuum. These findings demonstrate that cognitive measures differ markedly in their sensitivity across the AD continuum. Characterizing when specific measures become abnormal provides a framework for stage-appropriate test selection in clinical practice, improving clinical interpretation while informing the choice of cognitive endpoints and inclusion criteria in clinical trials.