This distinction is even more important when developing immunotherapeutic approaches to tau, specifically when determining the appropriate tau epitope to target for clearance. Although robust assays that can measure some forms of tau found in CSF and blood, these tau species do not necessarily represent the relevant pathological tau found in the brain parenchyma. Therefore, antibodies could target the correct disease relevant tau epitope in the brain but if the epitope is absent from CSF and blood, it is impossible to measure target engagement, making the clinical development of such antibodies extremely difficult. Several PET ligands are being tested, but not without challenges. Longitudinal tau tracer studies will further inform on the kinetics of tau aggregation, but current results from these studies and evidence from post-mortem Braak staging indicate that the rate of aggregation is likely slow and may be challenging to use as a proximal pharmacodynamic biomarker.
