Generally, positive preclinical pharmacokinetic data supports further development, but showing a pharmacodynamic effect in the preclinical stage in neurodegenerative tauopathies has been difficult to translate in the clinical setting. One root of the problem is the poor translatability of animal models to the human condition. These models often focus on overexpression of a single mutant tau isoform and would only recapitulate one particular tertiary and quaternary filament structure which are not relevant to all tauopathies. It is postulated that tau filaments present distinct ultrastructural polymorphs in different tauopathies. [23,24] Therefore, therapeutic agents optimized against a particular conformation may not be generalizable to all tauopathies broadly, posing a significant limitation for aggregation inhibitors and neutralizing antibodies which target a particular aggregation domain or epitope. Broad application and cross-purposing of therapeutics may prove problematic, and perhaps specialized therapeutics need to be developed for 3R- and 4R-tauopathies.
