Cerebrospinal fluid α-synuclein adds the risk of cognitive decline and is associated with tau pathology among non-demented older adults

Background The role of alpha-synuclein in dementia has been recognized, yet its exact influence on cognitive decline in non-demented older adults is still not fully understood.Methods A total of 331 non-demented individuals were included in the study from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants were divided into two distinct groups based on their alpha-synuclein levels: one with lower levels (alpha-synuclein-L) and another with higher levels (alpha-synuclein-H). Measurements included neuropsychiatric scales, cerebrospinal fluid (CSF) biomarkers, and blood transcriptomics. The linear mixed-effects model investigated the longitudinal changes in cognition. Kaplan-Meier survival analysis and the Cox proportional hazards model were utilized to evaluate the effects of different levels of alpha-synuclein on dementia. Gene set enrichment analysis (GSEA) was utilized to investigate the biological pathways related to cognitive impairment. Pearson correlation, multiple linear regression models, and mediation analysis were employed to investigate the relationship between alpha-synuclein and neurodegenerative biomarkers, and their potential mechanisms affecting cognition.Results Higher CSF alpha-synuclein levels were associated with increased risk of cognitive decline and progression to dementia. Enrichment analysis highlighted the activation of tau-associated and immune response pathways in the alpha-synuclein-H group. Further correlation and regression analysis indicated that the CSF alpha-synuclein levels were positively correlated with CSF total tau (t-tau), phosphorylated tau (p-tau) 181, tumor necrosis factor receptor 1 (TNFR1) and intercellular cell adhesion molecule-1 (ICAM-1). Mediation analysis further elucidated that the detrimental effects of CSF alpha-synuclein on cognition were primarily mediated through CSF t-tau and p-tau. Additionally, it was observed that CSF alpha-synuclein influenced CSF t-tau and p-tau181 levels via inflammatory pathways involving CSF TNFR1 and ICAM-1.Conclusions These findings elucidate a significant connection between elevated levels of CSF alpha-synuclein and the progression of cognitive decline, highlighting the critical roles of activated inflammatory pathways and tau pathology in this association. They underscore the importance of monitoring CSF alpha-synuclein levels as a promising biomarker for identifying individuals at increased risk of cognitive deterioration and developing dementia.