A significant challenge is demonstrating target engagement and selecting an appropriate dose. Even when a potential drug has a known mechanism, demonstrating target engagement to evaluate efficacy remains challenging, and a critical gap in tau drug development as a whole is the lack of appropriate biomarkers for target engagement and pharmacodynamics. Despite the term “tau” often used interchangeably, many populations of tau species exist in dynamic equilibrium. Few human biomarkers are available to distinguish between the transcriptional splice variants (3R/4R); how tau has been post-translationally modified (phosphorylated, O-GlyNAcylated, acetylated, ubiquitinated, truncated); whether it is exists as a soluble protein, an oligomer, or has been deposited as part of an insoluble aggregate; and where the particular tau species is localized (intracellular compartments, extracellular space, circulating in the CSF, released into the blood). Each of these tau populations is distinct though related, and the exact pathologic species is a matter of intense debate and are very likely different in the diverse tauopathies. [126]
