Abstract
Brain-derived tau (BD-tau) is a promising blood-based biomarker for neurodegeneration/brain injury in neurodegenerative and acute neurological disorders. However, widespread use is hampered by lack of commercial assays. Using the Simoa® HD-X analyzer, we evaluated the first commercial research-use only BD-tau Advantage PLUS assay’s robustness, precision, spike recovery, specificity, dilution linearity, and limit of detection. Matrix effect was examined by comparing BD-tau levels in n = 48 plasma/serum and n = 20 plasma/CSF sample pairs. Clinical performance was examined in a traumatic brain injury (TBI) cohort. Twenty repeated measurements of three plasma samples gave intra- and inter-plate coefficient of variation (CV) ≤ 7.24%. Analytically, BD-tau concentrations decreased linearly up to 16-fold dilution, spike recovery was 86–96%, and signals were highly specific to the CNS-abundant recombinant tau-441 but not the peripherally-enriched “big-tau” isoform. Moreover, signals were stable for up to four freeze/thaw cycles. Furthermore, there were significant correlations between plasma/serum (r = 0.8392; p < 0.0001) and plasma/CSF (r = 0.6150; p = 0.0039) pairs. Finally, plasma BD-tau was elevated in severe-acute TBI vs. chronic-mixed TBI and unaffected controls (p < 0.0001; AUC = 0.9986, and p < 0.0001; AUC = 1.000, respectively). In severe-acute TBI patients, plasma BD-tau was correlated with plasma p-tau217 (r = 0.5761, p = 0.0005), NfL (r = 0.8910, p = 0.0001), and GFAP (r = 0.5424, p = 0.0011). CSF BD-tau and CSF p-tau217 were strongly correlated (r = 0.9667, p = 0.0002). BD-tau Advantage PLUS produces robust brain-derived tau-specific readings that demonstrate utility in detecting severe-acute TBI. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-40271-6.