Abstract
INTRODUCTION: This study aimed to delineate trajectories of biomarkers-amyloid beta (Aβ), phosphorylated tau, neurodegeneration, and inflammation-and to identify change points along these trajectories. METHODS: Longitudinal data were collected over 30 years from 349 cognitively unimpaired individuals enrolled in the Biomarkers for Older Controls at Risk for Dementia study. Piecewise regression models were used to identify change points in cerebrospinal fluid biomarkers, brain magnetic resonance imaging volumes, and a composite measure of global cognition. RESULTS: Eighty-two participants progressed to mild cognitive impairment or dementia during the follow-up period. Change points were identified in years prior to clinical symptom onset: Aβ at -17.1 years, phosphorylated tau at -15.8 years, neurofilament light chain and whole-brain white matter at -11.6 years, and total ventricles at -9.7 years. CONCLUSION: These findings support the temporal sequence proposed by the dynamic biomarker model of Alzheimer's disease and underscore the significance of white matter degeneration as an early marker for disease progression in the pathological cascade. HIGHLIGHTS: Data were collected from 349 participants in Biomarkers for Older Controls at Risk for Dementia, a 30-year cohort study. Eighty-two participants progressed to mild cognitive impairment or dementia over an average of 11 to 12 years. Core cerebrospinal fluid biomarkers for Alzheimer's disease began to accelerate 15 to 20 years before clinical onset. Magnetic resonance imaging volumes accelerated with variations across brain structures. Volumetric changes in the white matter and ventricles preceded the hippocampus.