Discussing Anti-Amyloid Therapies in Alzheimer’s Disease

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In “Beyond Diagnosis: Alzheimer’s Disease,” Cleveland Clinic behavioral neurologist Jagan Pillai, MD, PhD, and host Glenn Campbell continue their discussion on communicating effectively with patients and families facing a progressive neurodegenerative illness.

Each monthly installment examines an aspect of Alzheimer’s disease care, including diagnosis, prognosis, treatment decisions, and ongoing support for patients and caregivers.

This third of six episodes focuses on how clinicians evaluate candidates for anti-amyloid therapies, set realistic expectations about benefits, and guide patients through complex decisions around risks, monitoring, and treatment duration.

The following is a transcript of their remarks:

Campbell: Welcome to “Beyond Diagnosis,” where we talk with doctors about talking with patients. I’m your host, Glenn Campbell. Alzheimer’s disease is a relentless, incurable, and eventually fatal illness that poses profound challenges for patients, families, and clinicians.

Today, we’ll explore how a behavioral neurologist approaches diagnosis, therapy, prognosis, and management of Alzheimer’s many complexities. Our guest is Dr. Jagan Pillai, who directs Cleveland Clinic’s Center for Brain Health. Dr. Pillai, thanks so much for being here.

Pillai: Thank you, Glenn, for having me.

Campbell: New amyloid-targeted therapies are raising hopes as well as questions. Lecanemab [Leqembi] and donanemab [Kisunla] were approved by the FDA in the past few years to treat early stage Alzheimer’s by removing amyloid plaques in the brain. How do you determine if a patient is a candidate for these drugs?

Pillai: That’s a great question, because many families and patients come to us with this specific thing having heard about the promise of these new medications that have been approved. The field has coalesced around some specific guidelines that determine whether it’s safe for a person to get the medication or not. Primarily, the safety of these medications are driven by some common side effects that come from these medications. They include, most notably, some microbleeds in the brain or some brain swelling that may happen and the fact that, when you’re on these medications, you cannot be on any anticoagulant therapy. I mean, we look at these patients and their medical history on the context of these three key things. So they may involve review of their brain scans to see if they have prior strokes, other comorbidities that may be impacting the use of these medications, the use of anticoagulant medications.

We also evaluate things like the genetic status for risks for this ARIA, or amyloid-related imaging abnormalities — that’s the microbleeds or the swelling that I mentioned. And also look at what are the patients and family’s goals going forward to make the final decision.

Campbell: How do you help ensure that patients and families have realistic expectations about how much benefit is possible with these drugs?

Pillai: Yeah, we need a cure for Alzheimer’s disease. It’s not there yet. So we would like to see that happen. These medications are not a cure. They try to remove the amyloid protein that’s one of the causes of Alzheimer’s disease and help slow down disease progression. So they’re called disease-modifying therapies. And the goal is that a person can maintain their level of functioning the way they are for a few months longer on these medications than they would if they’re not on the medications.

Campbell: Are you finding that patients and families who come to ask you about these drugs understand that it’s really just a matter of slowing progression or do they seem to sometimes have excessive expectations?

Pillai: It depends on where the families come from. Oftentimes people hope for the best, want the best. And it’s sometimes still a shock to see that there is clinical progression despite being on the medication. Resetting expectations, resetting goals that the fact that use of these medications does not prevent disease progression but slows things down is an ongoing conversation when they come in for their follow-up and see how a person’s doing over a period of time.

So I think eventually they are on board, but as they’re investing a lot and coming and getting the medications and the tests, they also buy into a lot about what the medication could or they want to see happen.

Campbell: These new medications specifically target amyloid, but we know that Alzheimer’s often involves other pathologies. Do these medications currently have a role for patients with a mixed pathology to their disease?

Pillai: That’s something a clinician carefully evaluates. If there are clinical symptoms of Parkinsonism or for Lewy body dementia, along with Alzheimer’s disease, or if they have other conditions like significant vascular disease, like strokes, or significant white matter changes that are impacting cognition, then those patients may not be great candidates for the anti-amyloid therapies as of now.

Campbell: You had mentioned brain bleeds, the risk of brain bleeds with these drugs, or what I understand are the so-called ARIAs, amyloid-related imaging abnormalities. How do you advise patients and families about the risk of these ARIAs that comes with these drugs?

Pillai: Yeah, that’s usually a key part of the discussion. The ARIAs are well-recognized side effects of these medications. So they have scheduled MRI scans that are part of the treatment protocol to evaluate for these ARIAs in the initial phases of the treatment when they’re more likely to happen. Second is to do APOE gene testing to see what is the risk for ARIAs.

So people carrying the APOE gene, especially the homozygotes — APOE4 and 4, have the highest risk of ARIA. And we usually recommend people or to consider seriously the possibility of them not taking the medication because of the higher risk. But even for people with the heterozygote or the APOE carrying one allele, they might have a higher risk and we try to give them a sense of what to expect going forward. So these kind of conversations happen before the medication is being provided to the patient, but also what to expect.

Being vigilant about any symptoms like headaches or dizziness or blurriness or fatigue more than expected, not to wait getting MRI imaging. And so these kind of proactive things that we do at our center also helps the patient and the family pick out early ARIA changes. And if you do notice them and if they’re moderate or severe, the medication regimen is stopped until the patient is better. Or if they’re not improving, then the medication may be discontinued.

Campbell: How might you handle a situation where your assessment of ARIA risk is greater than that of the patient and family, and they really want to try the drug, but you have greater concern about ARIA. Do you encounter that often? And if so, how do you manage that?

Pillai: As I mentioned, people getting the APOE4/4, the homozygotes, the gene have very high risk for ARIA. But sometimes people are highly motivated to taking the medication. There’s no clear FDA guidance on the fact that you should not be giving these medications to these APOE4 homozygotes.

So we have it honest conversations about, I would say about 90% of the time the family is recognizing the quality of life is more important rather than trying a medication. And if there is a risk to maintaining quality of life, maybe it’s better not to be on these antiamyloid therapies. Rarely, some families may go down the other choice going for the medications. In those cases, since everyone is aware of the risk, we try to proceed cautiously one infusion at a time.

Campbell: I understand that lecanemab and donanemab appear to be pretty similar in efficacy, but they haven’t yet been directly compared in a clinical trial. So how do you decide between these two agents for eligible patients?

Pillai: Yeah, that’s also a key topic of conversation, which one to go for. There is no clear guideline on that. So each physician team takes into account their experience how they manage the situation, patient’s expectations to formulate a plan that’s specific with the patient. What I have seen in general is that donanemab has a monthly infusion. So people who might have travel plans or who want more flexibility in the infusion schedule might choose that. Lecanemab has a biweekly infusion schedule, but they also have come up with now an auto-injector so the patients can take the medications at home. So that takes away some of the burden of that.

The second point of conversation is the fact that donanemab currently after 18 months, it’s discontinued; whereas lecanemab can be continued further than that. People who want a limited duration of treatment, that’s also a reason to go for donanemab, but people who want to consider all avenues to prevent even future amyloid buildup from happening, and they’re willing to invest in this longer term, maybe lecanemab is a better option for them.

And the last is, what is the risk factor for APOE and the ARIA risk for these two conditions? I mean, this field is evolving and right now they’re both comparable with the modified dosing that’s available on donanemab. So these are some of the key discussions we might have.

Campbell: In those cases where a patient is on lecanemab, how do you decide when to discontinue therapy and how do you explain your rationale to patients?

Pillai: Yeah, that’s also a key part of the discussion before they start the treatment, what to expect and why this may be discontinued. So one in five patients would not benefit from the medication, which means that even if they take the medication, the medication does not do a good job in removing the amyloid to a degree that’s beneficial or getting to the normal levels.

So we do a follow-up PET scan around month 12 or month 18, depending on which medication we use, to see if there is the medication working for them, what to expect. And by month 18, when the medication, the first part of the medication regimen is over, if we are not seeing a clear removal of the amyloid plaque to the degree that’s needed to get to within the normal range of things, we discontinue the medication and let the patients know why this is happening.

If they are on donanemab, the medication is also discontinued at the end of 18 months. The third reason why they may be discontinued if they have more noticeable side effects from medication, the ARIAs are significant enough that it’s not safe to continue the medication anymore.

Campbell: This recent progress we’ve seen in the development of new medications is very welcome, but can you tell us what else patients and families can do to help preserve their quality of life with Alzheimer’s?

Pillai: Yeah, absolutely. I think there is a lot of focus on medications, but what we have seen through parallel studies is that some non-medication options have beneficial effects almost to the same degree of some of these medications. Some beneficial effects that have been clearly documented are like, for example, making sure the person is in good medical health, so they have no other medical comorbidities that may be impacting their function, like uncontrolled diabetes or blood pressure problems.

The second could be physical activity. It’s been very clearly demonstrated that your physical activity profile helps you maintain your independence, avoid hospitalizations, and also maintain your quality of life going forward. And the effect size is pretty good compared to some of the medications. Diet is something that we always talk about. It’s something to be mindful of what you’re having so that it’s healthier for your brain and your heart.

So green leafy vegetables, nuts, white meat or fish, stopping or reducing significantly fried food or red meat. These are some changes that are very natural for some of our patients; for others, it’s a struggle. So recognizing that the impact of this is as good as medications sometimes changes the direction of their focus going forward.

Campbell: Thanks for your insights, Dr. Pillai. And thank you for joining us on “Beyond Diagnosis,” where we explore not just what physicians know, but how to effectively and compassionately share that knowledge with patients. See you next time.