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.