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

Abstract 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 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. 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 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 plasma assay, the first functional assay to detect pTau binding to recombinant normal tau using a tagged-tau chemiluminescent readout. Seventy-nine cognitively unimpaired (CU) and 66 cognitively impaired older adults underwent blood sampling, cognitive assessment, amyloid-PET or cerebrospinal fluid analysis, and [ 18 F]-MK6240 tau-PET imaging. Plasma pTau217 concentration was also quantified using the Lumipulse platform (Fujirebio). 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). Both cross-sectional values and annual changes in VeraBIND Tau were associated with cognitive performance and entorhinal tau-PET signal (all absolute r s ≥0.23, p