Plasma pTau181 and amyloid markers predict conversion to dementia in idiopathic REM sleep behaviour disorder

Blood-based biomarkers for Alzheimer's disease (AD) pathology have been intensively investigated as markers for AD-related neurodegeneration. Comorbid AD pathology is common in dementia with Lewy bodies (DLB). Accordingly, we hypothesized that plasma biomarkers associated with AD pathology might be useful to predict DLB in a cohort of idiopathic/isolated REM sleep behavior disorder (iRBD), an incipient synucleinopathy. The aim of this study was to determine whether plasma amyloid-β and pTau181 biomarkers can predict DLB. This longitudinal single-center (Canada) cohort study included 158 polysomnography-confirmed iRBD individuals between September 2004 and October 2022, each providing blood plasma samples, who were then offered prospective follow-up. Plasma Aβ40, Aβ42 and pTau181 levels were measured using NeuroToolKit, a prototype assays panel of neurodegeneration (Roche Diagnostics International Ltd). The primary outcome was the association between plasma biomarkers at baseline and eventual development of DLB. Correlations between plasma markers and baseline cognitive tests were assessed. A total of 142 iRBD participants (109 men [77%], mean ± SD age, 67.6 ± 8.0 years) were included in the final analysis. On prospective follow-up (2.9 ± 2.1 years after sampling), 32 individuals phenoconverted to a defined neurodegenerative syndrome (18 DLB, 13 PD, 1 MSA). The combined phenoconvertor group had lower baseline plasma Aβ42/40 ratio compared to non-phenoconvertors (mean ± SD, 0.103 ± 0.010 vs. 0.114 ± 0.012, p < 0.001), and higher pTau181 levels (0.993 ± 0.354 vs. 0.784 ± 0.266pg/ml, p = 0.008). When divided by phenoconversion subtype, significant differences were seen selectively in DLB-convertors (Aβ42/40 = 0.101 ± 0.010, difference -0.011, 95% CI [-0.016; -0.005], p < 0.001; pTau181 = 1.144 ± 0.326 pg/ml, difference 0.282 pg/ml, 95% CI [0.146; 0.418], p < 0.001). Cross-sectional analysis showed that plasma pTau181 (but not Aβ42/40) correlated with cognitive tests across various domains. Our results indicate that plasma Aβ42/40 ratio and pTau181 can predict conversion to DLB in iRBD.