Alzheimer Disease: Other Therapies Under Investigation

Alireza Atri, MD, PhD: Amyloid is 1 mechanism, but it’s not the only mechanism. What are some other mechanisms, Marc, that should be explored? Are there some data for which there may be hope that they may be efficacious or going into phase 2 or phase 3 trials?

Marc E. Agronin, MD: There are dozens of other studies that have been going on, and thankfully we do have a relatively large pipeline of studies, particularly for Alzheimer disease. One area has looked at secretase inhibitors, trying to inhibit the enzyme that leads to the formation of the toxic form of beta amyloid in the first place. There have been a number of different studies looking at that. To date, efficacy has not been proven. And so the future of those particular studies remains unclear.

A number of different experimental agents are looking at different ways to offer some neuroprotection. Even if we are unable to stop the buildup of amyloid and tau, is there a way that we can protect the cells? Is there a way we can reduce inflammation, which appears to cause so much of the damage? And so there are a number of different agents that have looked at that.

There have been some strategies using agents that are often used for diabetes to try to boost the metabolism of brain cells and see if that can have some impact on the course of the disease as well. So there are lots of ongoing issues. I think we know this is a complex disease, and it’s really slow growing. The failures of some of the major studies have been disheartening, but lots of different mechanisms are being explored. Whether it’s 1 or a combination of these, hopefully something will yield some really robust findings in the near future.

Alireza Atri, MD, PhD: That’s good. I’ll bring it back to you, Brad. You know, frontotemporal disorders oftentimes involve different forms of tau. And of course there’s a different kind of tau involved with Alzheimer disease. What are some approaches that are being looked at for Alzheimer disease and tau?

Bradford C. Dickerson, MD: The portfolio of compounds and strategies to target pathologic forms of tau protein is growing, which is nice to see. Whether it’s Alzheimer disease or whether it’s the primary tauopathies, we really need that tool in our tool kit.

So monoclonal antibodies. The initial thought was, how can you use a monoclonal antibody if the problem with tau is inside the cell—intracellular? But it turns out that this is where this hypothesis about the trans-synaptic spread of tau comes in. If tau is actually pathologic, hyperphosphorylated, tau is released from the synapse and crosses to the next cell. That may be the basis of its spread. There’s a chance to intercept it with a monoclonal antibody. And so that strategy is being tested. There are a variety of other small-molecule strategies that are being tested to try to see if you can reduce the process of hyperphosphorylation, potentially through modulating enzyme function, or potentially find other ways to clear out the pathologically hyperphosphorylated forms of tau, so they don’t keep spreading and depositing as tangles or the forms that we see in the frontotemporal disorders as well.

Alireza Atri, MD, PhD: It sounds as though all of these now, that we’re developing for our armamentarium of biomarkers, are going to be very, very useful in actually measuring those processes and having them be sort of targeted.

Transcript edited for clarity.