Day, Gregory S.

Abstract INTRODUCTION β‐synuclein is a promising blood marker to track synaptic degeneration in Alzheimer's disease (AD) but changes in preclinical AD are unclear. METHODS We investigated serum β‐synuclein in 69 cognitively unimpaired mutation non‐carriers, 78 cognitively unimpaired AD mutation carriers (asymptomatic AD), and 31 symptomatic mutation carriers from the Dominantly Inherited Alzheimer Network. RESULTS β‐synuclein levels were already higher in asymptomatic AD mutation carriers compared to non‐carriers and highest in symptomatic carriers. Longitudinal trajectories and correlation analyses indicated that β‐synuclein levels start to rise after amyloid deposition preceding axonal degeneration, brain atrophy and hypometabolism, and cognitive decline. β‐synuclein levels were associated with cognitive impairment and gradually increased with declining cognition. DISCUSSION Our study supports the use of blood β‐synuclein to track synaptic changes in preclinical AD and as a surrogate marker for cognitive impairment which might be used in early diagnosis and to support patient selection and monitoring of treatment effects in clinical trials. Highlights Blood β‐synuclein levels were already higher in asymptomatic Alzheimer's disease (AD) mutation carriers. Blood β‐synuclein levels were highest in symptomatic AD mutation carriers. Blood β‐synuclein levels start to rise 11 years before symptom onset. Rise of β‐synuclein precedes axonal degeneration, brain atrophy, and cognitive decline. β‐synuclein levels gradually increased with declining cognition.