Divergent patterns of cognitive decline in preclinical Alzheimer's disease: Implications for secondary prevention trials

INTRODUCTION: Biomarkers identify Alzheimer's disease pathology in cognitively unimpaired adults, but the timing and rate of cognitive decline vary widely. This study aimed to identify subgroups of cognitive decline and baseline predictors of heterogeneity in preclinical progression. METHODS: Data were drawn from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study, which enrolled amyloid beta-positive (Aβ+) participants, and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study, which enrolled amyloid beta-negative (Aβ-) individuals. Latent class mixed-effects models identified cognitive trajectory classes. Associations between class membership and demographic, clinical, and biomarker variables were evaluated. The primary outcome was change in the Preclinical Alzheimer Cognitive Composite. RESULTS: Three trajectory classes were identified: stable, slow decliners, and fast decliners. Higher phosphorylated tau at 217 (p-tau217), smaller hippocampal volume, and elevated tau positron emission tomography were associated with declining classes. About 70% of Aβ+ individuals were stable. DISCUSSION: Latent class modeling reveals substantial heterogeneity in preclinical trajectories with important implications for prevention trial design.