Considerations Around the Use of Anti-Amyloid Agents for Alzheimer’s Disease (Podcast)

“There has long been a sort of therapeutic nihilism around the management of Alzheimer’s disease,” says Charles Bernick, MD, MPH. “I’m hopeful that’s beginning to change with the availability of the new anti-amyloid monoclonal antibodies for Alzheimer’s disease, particularly regarding the importance of early diagnosis. It’s certainly the case that the earlier you start these drugs, if a person’s a candidate for them, the more likely they’re going to derive a benefit.”

In the latest episode of Cleveland Clinic’s Neuro Pathways podcast, Dr. Bernick, a staff neurologist with the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, shares an expert perspective on how the new anti-amyloid medications are being used in clinical practice. He addresses the following, among other topics:

• Amyloid's role in Alzheimer’s disease and why it’s a target for treatment
• How the anti-amyloid drugs work, and their impact on disease progression
• Criteria for identifying appropriate patients for anti-amyloid therapy, including use of amyloid PET and CSF testing
• Monitoring for and managing amyloid-related imaging abnormalities (ARIAs)
• Considerations around restarting treatment after ARIA events
• Potential for combination therapies targeting amyloid and tau proteins
• Current and upcoming clinical trials exploring new treatment approaches

Click the podcast player above to listen to the 28-minute episode now, or read on for a short edited excerpt. Check out more Neuro Pathways episodes at clevelandclinic.org/neuropodcast or wherever you get your podcasts.

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Excerpt from the podcast

Podcast host Glen Stevens, DO, PhD: Suppose I’m a patient who’s an interested and appropriate candidate for anti-amyloid therapy. How do you decide which of the two available drugs — lecanemab or donanemab — you start me on?

Charles Bernick, MD, MPH: Well, they both remove amyloid plaque, and even though there are no head-to-head trials, it seems like they provide similar benefit based on the scales that are used to assess response. So then it comes down to practical and theoretical reasons.

The practical piece is that donanemab is a once-a-month therapy that is stopped once all the amyloid is removed. That is based on the studies. The idea is that you do an amyloid scan maybe after the first year to see if the amyloid's gone. If it is, you can stop therapy. In contrast, lecanemab is a twice-a-month therapy given for 18 months. Now the other difference is that the ARIA rate is higher with donanemab, although rates of significant ARIA, which is a more severe ARIA, are the same. So if you are primarily worried about the worst of the worst ARIA effects, the drugs are about the same.

Then there are the theoretical aspects, like the fact that donanemab is targeted strictly to the amyloid plaques. There is some belief that the toxic form of amyloid is not the plaques themselves but rather what are called protofibrils, or a soluble form of amyloid, which lecanemab actually binds to. So if you go that route you would say, well, lecanemab is not only removing plaques, it also is removing this toxic soluble form. Which is why the company that produces lecanemab has gone to the FDA and is awaiting a decision on approval for maintenance therapy. The idea is that once you remove the plaque, the disease is still there, so amyloid production is going to start again and the disease will continue. The argument is that lecanemab could actually help in a maintenance phase after the plaque has been removed.

Dr. Stevens: I imagine some families feel comfort just from having their loved one undergo treatment, so I guess that when the doctor one day says, “It’s time to stop therapy,” that might cause some unease. It’s good to hear that there may be a decision on maintenance treatment, but how do patients and families generally take it when you say, “We're going to stop your treatment now”?

Dr. Bernick: Because these drugs were approved so recently — lecanemab in July 2023 and donanemab in July 2024 — we are just now starting to have people finishing their therapeutic regimen with lecanemab. So we don't know how they'll take the news or how many patients will have their amyloid fully removed. But I think there probably will be a certain comfort to know that, yes, the treatment has removed your amyloid plaques.

This brings up a larger issue, too. We think that amyloid is an important part of the disease, but it’s only one target within a very complex disease. There is a lot of work going on to evaluate drugs that target other mechanisms in the disease. It's likely there will be some combination therapy type of approach before too long.