Phosphorylated Tau at Threonine 181 Is Elevated in Amyotrophic Lateral Sclerosis Plasma

Reliable biomarkers for amyotrophic lateral sclerosis (ALS) remain limited. Although previous studies have shown altered cerebrospinal fluid (CSF) tau measures in ALS, the clinical relevance of plasma tau species as biomarkers remains unclear. Here, we sought to determine whether total tau, tau phosphorylated at T181 (pTau-T181), and their ratio are altered in ALS and whether these measures correlate with disease progression.

Plasma samples were obtained from two independent cohorts from the Northeast ALS Consortium (NEALS) Biofluid Repository (cohort 1: n = 76 ALS and n = 52 healthy controls [HC]; cohort 2: n = 98 ALS and n = 90 HC). Cohort 1 (mean age ALS 61.8 years; 63% male) included longitudinal samples; cohort 2 (mean age ALS 45.8 years; 51% male) was cross-sectional. Tau measures were quantified using Quanterix Simoa (cohort 1) and Meso Scale Discovery (MSD) (cohort 2) platforms.

In cohort 1, total tau was lower in ALS versus HC (0.88 vs. 1.49 pg/mL), whereas pTau-T181 (30.29 vs. 12.97 pg/mL) and pTau-T181:tau ratio (52.07 vs. 13.18 pg/mL) were higher. In cohort 2, total tau (40.07 vs. 25.85 pg/mL), pTau-T181 (6.77 vs. 2.18 pg/mL), and their ratio (0.37 vs. 0.098 pg/mL) were elevated in ALS. Plasma measures in cohort 1 did not correlate with decline on the revised ALS Functional Rating Scale (ALSFRS-R). Brain-derived tau (BD-tau) was elevated in ALS (10.07 vs. 5.65 pg/mL) in a subset of samples from cohort 1.

Collectively, plasma pTau-T181 levels are consistently elevated in ALS, supporting future studies to define its potential utility as an ALS biomarker.