Fluid Biomarkers for the Antemortem Detection of Chronic Traumatic Encephalopathy: A Critical Review

Chronic traumatic encephalopathy (CTE) is a progressive tauopathy associated with repetitive head impacts (RHIs) and is currently confirmed only at autopsy. The absence of a validated antemortem diagnostic limits individual risk assessment, clinical trial enrollment, and differentiation from disorders such as Alzheimer’s disease (AD). This review critically evaluates five candidate fluid biomarkers: phosphorylated tau (p-tau), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), and soluble TREM2 (sTREM2). For each, the review assesses the biological mechanism, CTE/RHI-specific evidence, diagnostic performance, and major confounders. None currently provides CTE-specific discrimination. In the largest cohort, plasma p-tau217 tracked amyloid status rather than CTE pathology. NfL reflects axonal injury but is nonspecific and strongly age-dependent. GFAP is associated with clinical CTE certainty in football and combat-sport cohorts, although not in an independent rugby cohort. S100B responds acutely to head impacts without a persistent cumulative signal. sTREM2 may reflect microglial activation that is bidirectionally related to tau after RHI exposure, but its primary case–control comparison was null. Short study windows may also be poorly matched to CTE’s multi-decade latency, and most evidence for p-tau, NfL and GFAP derives from one cohort, with the total tau, extracellular-vesicle and sTREM2 findings from a second. The review therefore emphasizes multi-marker panels, assay standardization, and longitudinal antemortem-to-autopsy cohorts as the validation work required before any fluid biomarker can support antemortem CTE detection.