Elevated Plasma Phosphorylated Tau 181 in Amyotrophic Lateral Sclerosis

Abstract

Objective Plasma phosphorylated tau (p‐tau 181 ) is reliably elevated in Alzheimer's disease (AD), but less explored is its specificity relative to other neurodegenerative conditions. Here, we find novel evidence that plasma p‐tau 181 is elevated in amyotrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. We performed a detailed evaluation to identify the clinical correlates of elevated p‐tau 181 in ALS. Methods Patients were clinically or pathologically diagnosed with ALS (n = 130) or AD (n = 79), or were healthy non‐impaired controls (n = 26). Receiver operating characteristic (ROC) curves were analyzed and area under the curve (AUC) was used to discriminate AD from ALS. Within ALS, Mann–Whitney–Wilcoxon tests compared analytes by presence/absence of upper motor neuron and lower motor neuron (LMN) signs. Spearman correlations tested associations between plasma p‐tau 181 and postmortem neuron loss. Results A Wilcoxon test showed plasma p‐tau 181 was higher in ALS than controls ( W = 2,600, p = 0.000015), and ROC analyses showed plasma p‐tau 181 poorly discriminated AD and ALS (AUC = 0.60). In ALS, elevated plasma p‐tau 181 was associated with LMN signs in cervical ( W = 827, p = 0.0072), thoracic ( W = 469, p = 0.00025), and lumbosacral regions ( W = 851, p = 0.0000029). In support of LMN findings, plasma p‐tau 181 was associated with neuron loss in the spinal cord (rho = 0.46, p = 0.017), but not in the motor cortex ( p = 0.41). Cerebrospinal spinal fluid p‐tau 181 and plasma neurofilament light chain were included as reference analytes, and demonstrate specificity of findings. Interpretation We found strong evidence that plasma p‐tau 181 is elevated in ALS and may be a novel marker specific to LMN dysfunction. ANN NEUROL 2022;92:807–818