Impact of Plasma p‐tau181 on Cognition, Motor Phenotypes, and Disease Course in ALS

Phosphorylated tau181 (p-tau181), an Alzheimer's disease biomarker, was recently evaluated in amyotrophic lateral sclerosis (ALS). We investigated plasma p-tau181 in 202 ALS/ALS-FTD patients and 94 healthy controls, assessing cognitive performance, motor function, and longitudinal dynamics. Plasma p-tau181 and NfL were significantly elevated in ALS, with p-tau181 increasing over 1 year while NfL remained stable. Neither marker correlated with cognitive performance, and only NfL was associated with disease severity and progression. Plasma p-tau181 was higher in patients with predominant lower motor neuron involvement. The results indicate that p-tau181 reflects peripheral processes in ALS, providing a complementary, mechanistically distinct biomarker from NfL.