Tau pathological activity in plasma before the onset of symptomatic Alzheimer's disease

Alzheimer's disease (AD) and other tauopathies are characterized by the hyperphosphorylation of tau (pTau), leading to its aggregation in the brain, a process strongly predictive of neurodegeneration and future cognitive decline. Currently, tau positron emission tomography (PET) is the only validated method for detecting tau aggregates in vivo. However, its high cost, invasiveness, and limited accessibility restrict its use in clinical settings and preclude large-scale screening. Moreover, existing plasma biomarkers that quantify the level of pTau at specific sites (e.g., pTau217) have limited specificity for confirming AD-related tau aggregation, partly due to the heterogeneous and irregular phosphorylation patterns of pTau. Besides, the concentration of pTau is frequently elevated in the context of isolated amyloid-β pathology, which is less strongly associated with cognitive decline in the absence of aggregated tau. There is therefore an urgent need for a reliable and scalable blood-based biomarker of tau pathology. A key mechanism underlying AD tau pathology is the ability of pathologically active pTau (PA pTau) to bind to and seed normal tau, facilitating prion-like propagation of insoluble tau aggregates. Here, we assessed the diagnostic performance of the VeraBIND Tau assay, the first functional assay to detect PA pTau seeding activity in plasma. Seventy-nine cognitively unimpaired (CU) and 66 cognitively impaired older adults underwent blood sampling, cognitive assessment, amyloid-PET or cerebrospinal fluid (CSF) analysis, and [¹⁸F]-MK6240 tau-PET imaging. Plasma pTau217 concentrations were quantified using the Lumipulse platform (Fujirebio). The VeraBIND Tau assay isolated PA pTau from plasma and evaluated its ability to bind recombinant normal tau using a tagged-tau chemiluminescent readout. VeraBIND Tau demonstrated 94.2% sensitivity and 96.1% specificity for predicting tau-PET positivity (AUC=0.97). It outperformed plasma pTau217 in CU individuals (PPV=85.9%), regardless of the pTau217 threshold used (maximal PPV of 57.5% using the 0.256pg/mL pTau217 threshold). This higher VeraBIND Tau diagnostic accuracy was driven by early tau-PET stages (Braak-like tau-PET stages 1-3; AUC=0.96 vs. 0.74 for pTau217, p=0.003). Moreover, both cross-sectional values and annual changes in VeraBIND Tau were significantly correlated with cognitive performance and entorhinal tau-PET signal (all absolute Spearman r≥0.23, p<0.05). These findings highlight the strong potential of VeraBIND Tau as a scalable and accurate screening tool to detect AD tau pathology in the general population. The assay may also help enrich clinical trials with tau-PET positive CU individuals, enhance clinical diagnostic workflows and support monitoring of tau-targeted therapies. Future work should evaluate its utility in optimizing triage and early-intervention strategies.