Elevated plasma phosphorylated tau 181 in amyotrophic lateral sclerosis relates to lower motor neuron dysfunction

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 amytrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. We performed a detailed clinical evaluation to unravel the potential source of this unexpected observation. Methods Patients were clinically or pathologically diagnosed with ALS (n=130) or AD (n=82), or were healthy non-impaired controls (n=33). 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 (UMN) 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=3297, p =0.0000020), 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). CSF p-tau 181 and plasma neurofilament light chain (NfL) 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.