Early increase of the synaptic blood marker β-synuclein in asymptomatic autosomal dominant Alzheimer's disease

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.