Inhibition of Tau Aggregation as a Basis for Treatment and Prevention of Alzheimer’s Disease

Tau pathology in Alzheimer’s disease (AD) initiates early, before clinical symptoms are observed and before accumulation of extracellular amyloid-β. Tau aggregation is an autocatalytic process that does not depend on its phosphorylation and is highly correlated with clinical dementia. Tau aggregation inhibitors (TAIs) could provide the therapeutic means for treating AD. We have developed cell-free and cellular models and transgenic mice that model tauopathy and demonstrate the molecular basis for achieving pharmacological selectivity of TAIs. Methylthioninium chloride, the first selective TAI identified, has demonstrated efficacy in a phase 2 trial of AD on both clinical and functional molecular neuroimaging end points. This supports the potential for use of TAIs both for prevention and for treatment of the disease. Leucomethylthioninium is now in phase 3 trials of AD and behavioral-variant frontotemporal degeneration in order to confirm the concept of TAI therapy for these tauopathies.