Elevated serum β-synuclein predicts cognitive decline and progression to dementia

Background Synapses are essential for cognitive processes, and synaptic dysfunction is a hallmark of Alzheimer’s disease (AD). Beta (β)-synuclein, a homologue of alpha-synuclein, is a presynaptic phosphoprotein abundantly expressed in the brain. It has emerged as a promising candidate biomarker for synaptic dysfunction. However, its role in longitudinal clinical progression has not been fully elucidated. This study investigated the associations of serum β-synuclein levels with AD pathologies, cognitive performance and progression to dementia. Methods We examined 474 participants from the AD Neuroimaging Initiative cohort with serum β-synuclein measurements. 233 participants also had corresponding cerebrospinal fluid (CSF) AD pathology data. Multiple linear regressions, linear mixed-effects models and Cox proportional hazards models were applied to explore the associations of serum β-synuclein level with CSF AD pathologies, cognition and dementia risk. Results Higher serum β-synuclein levels were associated with greater CSF phosphorylated tau181 and total tau levels and lower β-amyloid (1–42) levels. Serum β-synuclein predicted worse baseline cognitive performance and a longitudinal decline in AD Assessment Scale-Cognitive Subscale 13, Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes scores. Participants with higher serum β-synuclein levels showed a greater progression to dementia over 84 months compared with those with lower levels. Furthermore, even after adjusting for AD pathologies, elevated β-synuclein levels were associated with increased risk of dementia. Conclusions Our findings underscore serum β-synuclein as a promising biomarker for AD progression and cognitive decline. Further research is warranted to clarify its role in the pathogenesis of AD and validate its utility in clinical settings.