Tau-based therapies for Alzheimer’s disease

Tau neurofibrillary tangles and amyloid-β plaques are the two main hallmarks of Alzheimer's disease (AD). In AD, tau undergoes conformational changes and subsequent seeding, aggregation, and trans-neuronal spreading, contributing to the propagation of tau pathology in the brain in a prion-like fashion. Notably, the progression of cognitive decline in AD correlates much better with tau pathology than with deposition of Aβ plaques. For decades, the development of potential therapies for AD has been centered in counteracting the formation of amyloid-β plaques, with complete failure in clinical trials. As a consequence, the focus of AD drug discovery has been switched toward tau. In this chapter, current tau-targeting therapies for AD are summarized, from tau-kinase inhibitors to acetylation inhibitors, microtubule stabilizers, aggregation inhibitors, monoclonal anti-tau antibodies or active tau vaccines. Special emphasis has been placed on the most promising therapeutic agents that have reached clinical trials.