Current Series: Advances In Management Of Alzheimers Disease

Ronald C. Petersen, MD, PhD: In keeping with the notion that we may not have thoroughly explored all avenues of the amyloid cascade hypothesis, just recently there has been discussion about a couple of new trials that will be launched aimed at earlier intervention into the amyloid cascade process.

For example, there’s a study that is funded by the National Institute on Aging, using the Alzheimer’s Clinical Trials Consortium, that will launch a study called A45. This means that 2 drugs will be evaluated. Individuals who are clinically normal but have amyloid in the brain will be eligible for this study. So again, normal people who have some amyloid, for whom we want to prevent their progression clinically.

They will first receive a drug that will reduce the amyloid in the brain—an antibody to reduce the amyloid in the brain. Once the amyloid levels are knocked down, a second drug will be introduced to keep them from forming new amyloid. So an antibody and a BACE [beta secretase] inhibitor will be used in sequence to see if you can knock the protein down and keep it low; and hopefully that will prevent the development of clinical symptoms. So that’s new thinking, new clinical design, moving in to what they call the preclinical space, meaning people have the amyloid protein in the brain, but they’re clinically normal.

Then there’s 1 additional study that’s being discussed that probably will be launched soon, and this refers to people who are just below the threshold for amyloid positivity with a PET [positron emission tomography] scan.

Thus far, we’ve been talking about people who had positive amyloid PET scans. But what about the people who are just under the threshold, who are at the cusp of developing more amyloid, which then may trigger the tau accumulation in the brain? So the thinking is, can we measure that process? Can we see when the amyloid is just starting to increase, and can we see the tau taking off with amyloid imaging again? That may set the stage for intervention with an anti-tau therapy or an anti-amyloid therapy, at that point.

So these are exciting trials still looking at the amyloid/tau processing cascade. I think this is certainly a viable option, in terms of trying to prevent the clinical symptoms of the disease.