β-synuclein levels were associated with cognitive impairment and gradually increased with declining cognition.<h4>Discussion</h4>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.<h4>Highlights</h4>Blood β-synuclein levels were already higher in asymptomatic Alzheimer's disease (AD) mutation carriers. The gene discussed is SNCB; the disease is early-onset autosomal dominant Alzheimer disease.