Could tau be a successful therapeutic target for Alzheimer’s treatment?

Abnormal tau protein is found in the neurofibrillary tangles found in nerve cells in the brain starting a few years before the onset of cognitive impairment in Alzheimer’s disease. Most drug trials attempting to slow or reverse Alzheimer’s disease to date have focused on removing beta-amyloid, an abnormal protein that starts to appear up to 20 years before cognitive impairment and has been thought to be the trigger for the initiation of formation of the tau-containing neurofibrillary tangles. Most trials of anti-amyloid medications have been disappointing, although there have been some hints that they may be helpful if started very early, before or just at the onset of cognitive impairment. Several trials of anti-amyloid monoclonal antibodies in this pre-symptomatic stage are currently in progress. Even the controversial aducanumab (Aduhelm) looks like it may be more effective if used very early.

Monoclonal antibodies directed at abnormal tau have also been disappointing with no significant slowing of cognitive impairment in several trials on subjects with early-stage Alzheimer’s. Frankly I never held much hope that anti-tau therapy would be effective.  By the time that the tau-containing neurofibrillary tangles appear, nerve cells are dying and the brain is shrinking.  I thought that disease-modifying medications could only be effective in the early stages of Alzheimer’s disease, before too many nerve cells die.  I may have been wrong.

In a phase 2 study of the anti-tau monoclonal antibody semorinemab in subjects with moderate Alzheimer’s dementia (MMSE score 16-21), those receiving active drug declined a statistically significant 44% less than placebo on one measure of cognition, the ADAS-Cog₁₁. However, on another measure, ADCS-ADL, in which a caregiver scores the participant on how they perform a variety of tasks, there was no difference. These results were released on August 31 by the companies involved and have not yet been published in a peer-reviewed journal, but they are a bit of a tease, especially since a previous trial of this drug in preclinical Alzheimer’s showed no benefit.  Maybe anti-tau medications will be effective, but only in the moderate stages of the disease.  I’m not holding my breath.  We have been disappointed before by drugs, eg. aducanumab, that showed great promise in phase 2 studies, but which failed or produced mixed results in phase 3 trials. Still, if these results hold up in larger phase 3 studies, it will be tremendously exciting to have an intervention that might slow progression of Alzheimer’s, even if started as late as the moderate stage of dementia.