Journal Article

The utility of plasma p ‐tau217 in former American football players at risk for chronic traumatic encephalopathy

Stein, Thor D., Mez, Jesse, Peskind, Elaine R., Tripodis, Yorghos, Rabinovici, Gil D., Barr, William B., Bernick, Charles B., McKee, Ann C., Wethe, Jennifer V., Balcer, Laura, Alosco, Michael L, Tanner, Jeremy A., Cummings, Jeffrey L., Reiman, Eric M., Dodick, David W., Shenton, Martha E., Palmisano, Joseph N., Zetterberg, Henrik, Martin, Brett, Cantu, Robert C., Banks, Sarah J, Miner, Annalise E., Blennow, Kaj, Adler, Charles, Groh, Jenna R., Asken, Breton M., Ashton, Nicholas J., Stern, Robert A.

2025

Overview

Background In vivo biomarkers that can detect long‐term neuropathologies from repetitive head impact (RHI) exposure are needed, especially for the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Here, we evaluated plasma p‐tau217 as a potential biomarker for CTE p‐tau pathology, and examined the concordance between plasma p‐tau217 and Aβ pathology in an at‐risk for CTE sample. Method The sample included 180 male former football players (120 professional, 60 college), and 56 asymptomatic men without RHI (i.e., controls). Participants completed blood draws, 18F‐florbetapir (Aβ+=SUVR≥1.10), and 18F‐flortaucipir PET. Traumatic encephalopathy syndrome (TES) diagnoses were made. Single molecule array for plasma p‐tau217 (ALZpath) was performed (≥0.6 cutoff used to maximize sensitivity). Nine participants had post‐mortem tissue. ANCOVA examined group differences in p‐tau217 (football vs controls; TES‐CTE no, TES‐CTE suggestive, TES‐CTE possible/probable). Multivariable regression models tested associations between p‐tau217 and florbetapir/flortaucipir PET. Covariates included age, race and APOE e4. Result Sample characteristics are in Table 1. p‐tau217 concentrations were higher in former football players compared to controls (est. marginal mean difference=‐0.217, p = 0.005). There were no group differences in Aβ‐PET SUVR. No differences were found across TES‐CTE certainty levels. In football players, higher p‐tau217 was associated with higher Aβ‐PET SUVR (B=1.380, 95%CI[0.597‐2.155], p = 0.001) but not when Aβ+ (n = 17) participants and those with kidney/liver disease (n = 5) were excluded. Aβ+ participants had the highest p‐tau217 (Figure 1). When compared against Aβ‐PET, several false Aβ‐positives (high p‐tau217, Aβ‐) were identified, including one extreme outlier (assay related) and a cluster of Aβ‐ participants with p‐tau217 between 0.60–1.0. There were no associations with flortaucipir SUVR (frontal, mesial temporal, left parietal). Two extreme p‐tau217 outliers had autopsy‐confirmed CTE stage III (AD‐, Table 2). Of the remaining donors, all were AD‐ and four had CTE (stages II‐IV) with ptau217 between 0.125‐0.449. Conclusion Plasma p‐tau217 has usefulness in quantifying Aβ pathology but restricted utility for detection of CTE. In this at‐risk for CTE sample, p‐tau217 and Aβ‐PET were associated at the group level. At the individual level, false Aβ‐positives (and negatives) existed, including Aβ‐ participants with high p‐tau217. We will explore whether this discrepancy is due to disease or peripheral interference with the N‐terminal binding in p‐tau assays.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: American football / Autopsy / Biological markers / Biomarkers / Chronic traumatic encephalopathy / Disease / Disorders / Donors / Encephalopathy / Football / Liver diseases / Pathology / Plasma / Race / Risk / Soccer / Trauma / Usefulness