TRAILBLAZER-ALZ3

A recurring theme of my blog has been that our best shot at attacking Alzheimer’s disease is in the earliest stage, before cognitive impairment has started. We now know that the first pathological signs of Alzheimer’s, the amyloid plaques, can be found up to 20 years before the start of cognitive decline. We also know that life style modifications such as aerobic exercise, adopting a Mediterranean-style diet, staying socially and intellectually active, getting at least seven hours of sleep, and managing cardiovascular risk factor such as high blood pressure, diabetes, and high cholesterol can significantly slow the progression and/or reduce the chance of getting Alzheimer’s disease, but only if adopted before the onset of dementia. Potential medications for Alzheimer’s that target amyloid in the brain have almost all failed in trials or, as in the case of aducanumab, produced conflicting and controversial results. However, most of these trials so far have used subjects who already have cognitive impairment or are in the lower part of the normal range.

Donanemab is one of the latest anti-amyloid monoclonal antibodies, and it has some characteristics that make it stand out from the others.  For one, it is by far the most effective in removing amyloid plaques.  And once the plaques are gone, they don’t seem to come back, even if the drug is stopped. So theoretically, donanemab might be used to induce amyloid removal and might not need to be continued. There also was a suggestion from the phase 2 study suggesting that subjects with the earliest disease had the best response in slowing cognitive impairment. Now a large, phase 3 study called TRAILBLAZER-ALZ3 is about to start in cognitively normal people at high risk for Alzheimer’s disease based on a positive test for plasma p-tau217. This blood biomarker has been shown to be very sensitive and specific for tau protein induced by amyloid in the brain, the hallmark of Alzheimer’s disease.

 I am really excited about this study. I would be the first to sign up if I were still cognitively normal. For me, the horses may already be out of the barn. It may be too late to stop the inexorable cascade of neurodegeneration in my brain eventually leading to dementia. But I think there is reason to hope, especially for those with Alzheimer’s disease who are still in the earliest stages of disease, before onset of cognitive impairment.