Plasma brain-derived tau and phosphorylated tau at T181 are elevated in amyotrophic lateral sclerosis

There is an unmet need for reliable biomarkers for amyotrophic lateral sclerosis (ALS). Recent studies demonstrated that the levels of the microtubule-associated protein tau are altered in plasma and cerebrospinal fluid (CSF) from people living with ALS. Our previous findings revealed that while the ratio between tau and phosphorylated tau at T181 (pTau-T181) is lower in ALS CSF compared to healthy controls (HC), higher CSF tau levels correlated with faster disease progression. Here, we measured total tau and pTau-T181 in plasma samples from two cohorts of participants with ALS and HC using two platforms: Quanterix Simoa and Meso Scale Discovery (MSD). Both assays demonstrated significantly higher pTau-T181 and pTau-T181:tau ratio levels in ALS compared to HC. Longitudinal analysis revealed that higher pTau-T181 levels at baseline correlated with faster decline on the revised ALS functional rating scale (ALSFRS-R). Although the MSD analysis revealed higher plasma tau levels in ALS, the Quanterix Simoa assay demonstrated lower total tau levels in ALS plasma than in HC. To investigate the source of this discrepancy, we measured brain-derived tau (BD-tau) using a new Quanterix assay that specifically detects tau originating from the central nervous system (CNS). This analysis demonstrated significantly elevated plasma BD-tau levels in ALS, mirroring the results obtained with the MSD assay, suggesting that the elevated plasma tau observed in ALS is primarily CNS-derived. Collectively, our data indicate that plasma BD-tau and pTau-T181 levels are elevated in ALS, and future studies will aim to define their potential utility as diagnostic or prognostic biomarkers.