Breakpoints in Alzheimer's disease biomarkers and cognition across the aging spectrum: The Mayo Clinic Study of Aging

INTRODUCTION: We examined when Alzheimer's disease biomarkers become informative by identifying age-related breakpoints with slope-changing trajectories. METHODS: In 2082 Mayo Clinic Study of Aging participants, we modeled plasma amyloid beta (Aβ)42/40, phosphorylated tau (p-tau)181, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), amyloid/tau positron emission tomography (PET), hippocampal volume (HVa), and global cognition. Generalized additive models described age trends; Davies' test and piecewise linear regression estimated breakpoints. A C2N subsample (n = 462) provided mass-spectrometry plasma markers (p-tau181, p-tau217, their ratios, Aβ42/40). RESULTS: In the full cohort, Aβ42/40, HVa, and cognition declined with age; p-tau181, NfL, GFAP, and amyloid/tau PET increased. We observed single breakpoints (years, 95% CI): GFAP 68.1 (63.5-71.8), NfL 70.7 (65.9-75.6), p-tau181 67.2 (60.3-70.3), amyloid PET 62.3 (56.2-69.3), HVa 68.1 (63.1-71.9), cognition 59.8 (55.4-66.0); tau PET showed none. In the mass-spectrometry subset, p-tau217 and p-tau181 broke at 72.6; their ratios and Aβ42/40 showed no breakpoints. DISCUSSION: Breakpoints cluster near late midlife, suggesting windows for screening and monitoring.