CSF total tau/alpha-synuclein ratio improved the diagnostic performance for Alzheimer's disease as an indicator of tau phosphorylation

Abstract

Background: Recently, several studies suggested potential involvements of alpha-synuclein in Alzheimer's disease (AD) pathophysiology. Higher concentrations of alpha-synuclein were reported in cerebrospinal fluid (CSF) of AD patients with a positive correlation towards CSF tau, indicating its possible role in AD. We analyzed the CSF biomarkers to verify whether alpha-synuclein could be an additional supported biomarker in AD diagnosis. Methods: In this cross-sectional study, CSF samples of 71 early-onset AD, 34 late-onset AD, 11 mild cognitive impairment, 17 subjective cognitive decline, 45 Parkinson's disease, and 32 healthy control (HC) were collected. CSF amyloid-beta 1-42 (A), total tau (N), and phosphorylated tau181 (T) were measured by commercial ELISA kits, and in-house ELISA kit was developed to quantify alpha-synuclein. The cognitive assessments and amyloid-PET imaging were also performed. Results: CSF alpha-synuclein manifested a tendency to increase in AD and to decreased in Parkinson's disease compared to HC. The equilibrium states of total tau and alpha-synuclein concentrations were changed significantly in AD, and the ratio of total tau/alpha-synuclein (N/alpha S) was dramatically increased in AD than HC. Remarkably, N/alpha S revealed a strong positive correlation with tau phosphorylation rate. Also, the combination of N/alpha S with amyloid-beta 1-42/phosphorylated tau181 ratio had the best diagnosis performance (AUC = 0.956, sensitivity = 96%, specificity = 87%). In concordance analysis, N/alpha S showed the higher diagnostic agreement with amyloid-beta 1-42 and amyloid-PET. Analysis of biomarker profiling with N/alpha S had distinctive characteristics and clustering of each group. Especially, among the group of suspected non-Alzheimer's disease pathophysiology, all A-T+N+ patients with N/alpha S+ were reintegrated into AD. Conclusions: The high correlation of alpha-synuclein with tau and the elevated N/alpha S in AD supported the involvement of alpha-synuclein in AD pathophysiology. Importantly, N/alpha S improved the diagnostic performance, confirming the needs of incorporating alpha-synuclein as a biomarker for neurodegenerative disorders. The incorporation of a biomarker group [N/alpha S] could contribute to provide better understanding and diagnosis of neurodegenerative disorders.