Cerebrospinal fluid α-synuclein predicts neurodegeneration and clinical progression in non-demented elders

Background: Accumulating reports have suggested that alpha-synuclein is involved in the pathogenesis of Alzheimer's disease (AD). As the cerebrospinal fluid (CSF) alpha-synuclein has been suggested as a potential biomarker of AD, this study was set out to test whether CSF alpha-synuclein is associated with other AD biomarkers and could predict neurodegeneration and clinical progression in non-demented elders. Methods: The associations between CSF alpha-synuclein and other AD biomarkers were investigated at baseline in non-demented Chinese elders. The predictive values of CSF alpha-synuclein for longitudinal neuroimaging change and the conversion risk of non-demented elders were assessed using linear mixed effects models and multivariate Cox proportional hazard models, respectively, in the Alzheimer's disease Neuroimaging Initiative (ADNI) database. Results: The CSF alpha-synuclein levels correlated with AD-specific biomarkers, CSF total tau and phosphorylated tau levels, in 651 Chinese Han participants (training set). These positive correlations were replicated in the ADNI database (validation set). Using a longitudinal cohort from ADNI, the CSF alpha-synuclein concentrations were found to increase with disease severity. The CSF alpha-synuclein had high diagnostic accuracy for AD based on the "ATN" (amyloid, tau, neurodegeneration) system (A + T+ versus A - T - control) (area under the receiver operating characteristic curve, 0.84). Moreover, CSF alpha-synuclein predicted longitudinal hippocampus atrophy and conversion from MCI to AD dementia. Conclusions: CSF alpha-synuclein is associated with CSF tau levels and could predict neurodegeneration and clinical progression in non-demented elders. This finding indicates that CSF alpha-synuclein is a potentially useful early biomarker for AD.