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

Objective Plasma phosphorylated tau (p-tau181) 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-tau181 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-tau181 and postmortem neuron loss. Results A Wilcoxon test showed plasma p-tau181 was higher in ALS than controls (W=3297, p =0.0000020), and ROC analyses showed plasma p-tau181 poorly discriminated AD and ALS (AUC=0.60). In ALS, elevated plasma p-tau181 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-tau181 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-tau181 and plasma neurofilament light chain (NfL) were included as reference analytes, and demonstrate specificity of findings. Interpretation We found strong evidence that plasma p-tau181 is elevated in ALS and may be a novel marker specific to LMN dysfunction. ### Competing Interest Statement LD receives consulting fees from Passage Bio and has received honoraria from the Muscular Dystrophy Association and National Society of Genetic Counselors. TFT has received research support from the Parkinson Foundation and The Michael J Fox Foundation. He has received consulting fees and honoraria from the Parkinson Foundation and Sanofi Genzyme. All other authors have no conflicts of interest to report. ### Funding Statement This work is supported by funding from the National Institute of Aging (P01-AG066597, U19-AG062418, P30-AG072979, R01-AG054519, R01-AG052943) and the Penn Institute on Aging. KAQC is supported by the Alzheimer's Association (AARF-D-619473, AARF-D-619473-RAPID) and P30-AG072979. TFT is supported by the NIH/NINDS (K23-NS11416-01A1). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of University of Pennsylvania gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request of qualified investigator to the authors.