AAIC Expert Insight: Can Alzheimer Disease Be Treated With a Single-Target Approach?

Maria C. Carrillo, PhD

At the 2022 Alzheimer’s Association International Conference, held July 31 to August 4, in San Diego, California, data from studies of 3 different interventions for Alzheimer disease (AD) were presented during a Focused Topic Session on August 2. These included an assessment of the investigational agents crenezumab (Roche) and T3D-959 (T3D Therapeutics), as well as data from a study of an exercised-based approach to cognitive decline.

The session included presentations from Eric M. Reiman, MD, executive director, Banner Alzheimer’s Institute; John Didsbury, PhD, founder and CEO, T3D Therapeutics; and Laura Baker PhD, associate professor of gerontology and geriatric, and internal medicine, Wake Forest University School of Medicine. The discussion was moderated by Maria C. Carrillo, PhD, chief science officer, Alzheimer’s Association. During the presentations, data from the crenezumab study, the phase 2 Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) Colombia trial (NCT01998841), revealed that the amyloid-ß oligomer-targeted treatment failed to meet either of its coprimary end points with significance, continuing a trend that has been observed with countless therapeutic approaches in AD.

As AD is a multifaceted disease, some have suggested that the so-called failures of Aß-targeted treatments could be in part because of their single focus. Now, with the 2021 approval of aducanumab (Aduhelm; Biogen), the field has stepped closer to the potential evaluation of therapies in combination. During the Focused Topic Session at AAIC 2022, NeurologyLive^® inquired with the panelists about their thoughts on such an approach being taken.

NeurologyLive^®: Dr. Carrillo mentioned the hope for precision medicine in AD, and some have suggested that a multipronged approach will be the best for AD treatment. In that vein, do you believe that the ultimate treatment of AD will be dependent on targeting multiple pathways at once, and is there potential that single-target approaches might never show the results that the field is hoping to achieve with Aß targeted therapies?

Maria C. Carrillo, PhD: I do believe that as we learn more about how we change underlying brain metabolism and proteins as we age, we will be able to see an incremental slowing of clinical decline, as we’ve seen now. Especially when we are treating people who already have memory disorders—they’re already starting down that path. So, we’re not yet using them [earlier] and we haven’t yet demonstrated that we can slow clinical decline with a prevention strategy, as is being studied with some clinical trials right now, including the A4 study. But that said, it's important to understand how each contributor—each treatment that targets a specific protein—can slow clinical decline because, ultimately, then when we can aggregate them, and they become additive, that's how other diseases have treated successfully. You start with one and understand what that one does and its contribution. Then, we continue to add.

John Didsbury, PhD: I think the complexity of the brain demands a solution that addresses that complexity. And that involves a systems biology approach to treating the disease as opposed to one-off specific targets. Not that they might not be partially effective, and that the combination of one-off specific targets may also work and provide a better treatment paradigm.

Laura Baker PhD: I would just say, too, adding on to the systems biology approach, it may be that interventions like exercise, or other lifestyle interventions, could basically be fertilizer for treatments that are pharmacologic in nature. I think we have just a lot of work to do and a lot of consideration that it may not be a single target. There are many things we can do to support this the biological substrate so that we might have more efficacious, pharmacologic response.

Eric M. Reiman, MD: As everybody else has said, I agree that ultimately there will be opportunities to look at combination treatments are sequential treatments that target earlier and later stages of the disease and have a more profound effect. The challenge we have, as Maria [Carrillo] noted, is that the science needs to get there. We need to have ways to be able to understand the individual adverse and beneficial effects and be able to put these studies to the test. What is happening over the last few years are tremendous learnings in how to do these treatment and prevention trials, which is going to benefit all of these different approaches.

Transcript edited for clarity. Click here for more coverage of AAIC 2022.