Chronic traumatic encephalopathy has long been a diagnosis confined to the autopsy table — invisible during life, confirmed only in death. If a reliable blood-based signal could indicate CTE-related pathology while patients are still living, it would fundamentally shift how clinicians approach former contact-sport athletes presenting with cognitive and behavioral decline.
This multicenter longitudinal case-control study, drawing from the DIAGNOSE CTE Research Project and involving 231 participants collected between 2016 and 2023, evaluated plasma phosphorylated tau 217 (p-tau217) as a potential in vivo biomarker for CTE neuropathology. Participants were predominantly former American football players — individuals with documented repetitive head impact (RHI) exposure — compared against unexposed male controls. P-tau217 levels were stratified into positive (≥0.63 pg/mL), intermediate (0.40–0.62 pg/mL), and negative (<0.40 pg/mL) categories. The study also cross-referenced p-tau217 against amyloid-beta PET imaging and tau-PET scans, and in a postmortem subsample, compared biomarker status directly against confirmed CTE neuropathology, controlling for age, race, and APOE ε4 genotype.
P-tau217 has attracted substantial attention in Alzheimer's disease research, where it performs with high accuracy in detecting amyloid and tau co-pathology. Its application to CTE is more complicated, however, because CTE's tau deposition follows a distinct anatomical pattern — perivascular and sulcal-depth-predominant — that differs mechanistically from the neocortical spread seen in Alzheimer's. This creates a genuine diagnostic challenge: p-tau217 may conflate CTE-related tau with Alzheimer's co-pathology, which frequently co-occurs in aging former athletes. The postmortem concordance subsample in this study is particularly valuable precisely because it allows researchers to anchor blood biomarker signals to confirmed tissue-level pathology rather than relying solely on imaging surrogates. Still, the study's all-male, predominantly American football cohort limits generalizability to female athletes or other contact sports. This work is best characterized as an important proof-of-concept that positions p-tau217 as one piece of a multimodal diagnostic framework rather than a standalone CTE screening tool.