The failure of several Phase II/III clinical trials in
Alzheimer's disease (AD) with drugs targeting β-
amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau
phosphatases/
kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a
drug existing in equilibrium between a reduced (
leuco-methylthioninium) and oxidized form (MT(+)). MT
chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and
biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of
frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called
TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by
salsalate, a clinically used derivative of
salicylic acid.