Plasma biomarker trajectories across Alzheimer’s clinical onset: a 17-year prospective study

BACKGROUND: Long-term trajectories of plasma biomarkers relative to clinical symptom onset in Alzheimer’s disease (AD) remain scarce. METHODS: We analyzed 17-year longitudinal data from 195 initially cognitively unimpaired participants in the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) study. Plasma biomarker trajectories were modeled as a function of years from estimated mild cognitive impairment (MCI) symptom onset using generalized additive mixed models. RESULTS: In participants who progressed to amyloid-positive MCI, plasma p-tau181/Aβ42 and GFAP diverged from stable controls earliest (about 13 and 12 years before symptom onset, respectively), followed by Aβ42/Aβ40, p-tau181, and NfL, all of which became abnormal before symptom onset. Individuals who developed amyloid-negative MCI showed abnormalities only in GFAP (about 11 years before onset) and YKL-40 (around the time of symptom onset). CONCLUSIONS: This study establishes a clinically anchored temporal map of plasma AD biomarkers. Plasma markers detect AD-related pathological changes more than a decade before symptom onset, offering a scalable, non-invasive approach for defining the preclinical phase and identifying at-risk individuals for early intervention.