Aging Now Podcast

Revolutionary Breakthrough In Alzheimer’s Treatment

• Season 1 • Episode 3

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0:00 | 26:43

A new class of drugs can now remove the protein behind Alzheimer's disease from the brain. But it doesn't restore memory. It doesn't cure the disease. And not everyone qualifies. So what does it actually do and who is it for?

 Dr. David Reuben and Dr. Alejandra Sanchez Lopez walk through everything families and patients need to know before considering anti-amyloid therapy  from eligibility criteria and side effect risks to what the clinical trial data really means in plain language.

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FEATURED PHYSICIANS
 
Dr. Alejandro Sanchez Lopez
Neurologist | UCLA Health
 
Dr. David Reuben
Geriatrician | UCLA Alzheimer's and Dementia Care Program

The information shared in this podcast is for educational purposes only and does not constitute medical advice. Please consult a qualified healthcare provider for guidance specific to your situation

SPEAKER_02

It doesn't cure the disease, but what they do is that they slow the progression of the disease.

SPEAKER_01

Here you you have a drug that actually takes out the biological marker of the disease and pushes it down the toilet. What do you tell people in terms of what they can expect from these drugs?

SPEAKER_00

On this episode, Dr. David Rubin sits down with Dr. Alejandra Sanchez Lopez, a cognitive impairment and behavioral neurology specialist. They're talking about the new drugs that can actually remove Alzheimer's protein from the brain and what that means for the millions of families watching someone they love start to forget.

SPEAKER_01

Hello, I'm Dr. David Rubin. I'm a geriatrician, and I'm delighted to be here today with Dr. Alejandra Sanchez Lopez, who is a very unique physician. So Alejandra, can you say just a little bit about your background? Because you're kind of a one-of-a-kind.

SPEAKER_02

Sure. Well, I um I did internal medicine right as I inmate residency. Um, and then I continue doing uh geriatrics. Um, but then I did another fellowship that was uh behavioral neurology. So basically I consider myself like a uh dementia or a cognitive impairment specialist.

SPEAKER_01

And you are. She has appointments in uh both uh neurology uh as well as in geriatrics. And she is the one of the people that I go to first when we talk about uh when I'm considering patients on the topic we're going to talk about, which is the anti-amyloid therapy. So um as a geriatrician, I see a lot of patients who have cognitive impairment and might be good candidates. But what what makes them good candidates?

SPEAKER_02

Right. So the the patients that we uh that benefit the most from this type of uh treatment, uh they're patients that have a diagnosis of uh mild cognitive impairment or mild dementia due to Alzheimer's disease. And the earlier the better, because those are the patients that benefit the most. And they do have to have uh some uh type of uh imaging or studies that uh ensure that they do have like the targeted uh protein, which is amyloid. So either an amyloid pet that is positive or in uh CSF.

SPEAKER_01

So these treatments are only for uh Alzheimer's disease, is that right?

SPEAKER_02

That is right. So if the if we are considering the the patient has uh diagnosis of uh cognitive impairment due to something else, uh then they wouldn't be uh good candidates because they wouldn't benefit from uh from this type of treatments. Also, if they have more advanced stages of Alzheimer's disease, like if they're moderate or severe, uh they wouldn't be a good candidate.

SPEAKER_01

And what do these drugs actually do?

SPEAKER_02

So uh they're uh monoclonal antibodies uh against uh amyloid. And what they do is that uh they target, they bind to amyloid to different species of amyloid. Uh we have two types of medications, lycanemab and donanemab. And lycanemab uh binds to uh a more soluble form of amyloid and donanemab to a more uh mature uh amyloid, a plaque. And after they bind, uh the there's an immune reaction uh that makes the microglia in the brain uh get uh clear the amyloid from the brain.

SPEAKER_01

So the amyloid actually goes away?

SPEAKER_02

It does go away. And actually the medications do that very well. Uh but we what we care about is the uh function, right, and the the cognition of the patient. And we know that the medications there uh they're for patients with Alzheimer's disease, but they it doesn't cure the disease. And I think that's important for uh patients and families to know. But what they do is that they slow uh the progression of the disease.

SPEAKER_01

So is anybody who has Alzheimer's disease eligible for these drugs? Or you know, are some people you said you already mentioned that people who are too far advanced wouldn't be good candidates. Uh but are other people who uh ineligible.

SPEAKER_02

There is a you know a list of uh exclusion criteria that we review uh for these patients. So we also have to think about not just who can benefit from the medication, but also who's at the risk of having side effects from the medication. So some patients that wouldn't be a good candidate, they wouldn't be a good candidate uh, for example, patients that are taking anticoagulation, uh would be one, or the patients that have uh uh changes in their brain uh due to vascular disease, if it if it's severe vascular disease, because that may be actually causing uh some of the cognitive improvement if they had uh a stroke or a TIA in the last uh one year, also uh seizures. And then um the other type of uh exclusion is if they had a seizure, uh especially if they had seizures uh in uh they're in adult adulthood, if they have uh have had seizures in their children, so that might be okay. Um but especially if they had a seizure in the last one year. And you know, I would say that we also want to think about the patients that have uh A4 uh homicidus. So not that they they're not good candidates, but we just have to pay attention to those patients because they are at risk of having uh an increased uh increased risk of having uh aminoid-related imaging abnormalities.

SPEAKER_01

So I'm interested in you well, the first thing that you said was uh people who are on anti-coagulation. And and you know why why would these drugs affect people who are on anticoagulation preferentially?

SPEAKER_02

So exactly you know, the same the the anti-am uh sorry uh uh aminoid-related imaging abnormalities, uh the aria, so either like it could be uh aria E for edema or aRIA H for hemorrhage. So one of the risks is uh swelling and bleeding in the brain. So if they're already at risk of having uh bleeding, right, uh so they're on anticoagulation, then uh and then they might be at risk of having aria H. So that is an adequate combination.

SPEAKER_01

Got it. So these uh how often do these side effects occur?

SPEAKER_02

So uh it depends on the status of the genotype. Uh so that's why we like to check actually uh the uh ApoE genotype. So we all have two alleles, right? From mom and from dad. So then we have um Apoe2, three, or four, right? And if we have uh two copies of ApoE4, that'd be the patient that have the highest risk. And it depends on which medication, but roughly I would say that uh if patients have two copies of ApoE4, they're about 20% of having uh ARIA. And then if they have one copy, 14%. Uh so lecanemap might have a different uh risk, but uh that's like the the rate for for donanemab. And um it actually the risk was less now that we have a different type of dosing. So there used to be a standard dose uh for donanemab, and then now we have a titration, uh modified uh dose titration with decreased uh the rate. The majority of patients that develop uh aria uh they don't have symptoms. So they were, you know, the in the trials, they found uh they had aria because they had uh frequent MRIs, right, as part of the study. And that's actually what we see in clinic in clinical care as well. Uh most patients do not have symptoms. And you know, if you know, if we do catch it in the in in an MRI, we can make changes to the treatment, right? Like suspend or make more frequent uh have them have more frequent MRIs.

SPEAKER_01

So in other words, if um if somebody has uh develops one of these complications like the edema, it could potentially they're they're not off the drug forever. They could get go back on the drug?

SPEAKER_02

If they have one of these complications?

SPEAKER_01

Yeah.

SPEAKER_02

So yeah, it depends on uh the severity. And and I want to clarify also that those percentages that I mentioned were for uh ARIA-E. And that's the one that we care most about, uh, because when um you look at the ARIA H, the patient had uh bleeding, uh only uh only bleeding without the edema, actually the the rate was about the same as placebo. So we care about either ARIA E on its own or ARIA E with hemorrhage. And um, in terms of what to do if they uh present, so if somebody has uh has no symptoms and they have their routine MRI, which they get about four MRIs in the first six months because that's when the the side effect, the aria happens more commonly initially. So if they had a uh in their MRI, then we uh categorize by severity in terms of mild, moderate, or severe. So if they have no symptoms and it's mild, then they can continue treatment, but then we have to do an MRI every month. So that's sort of the option, right? Now we have to talk about this uh with patients and families, right, to make them aware. And that's fine to do. I mean, we can also uh suspend treatment and recheck, but it is fine with no symptoms having mild aria to continue. Now, if somebody has uh symptoms or or no symptoms at all, but it's a severe uh aria, then we suspend treatment, we don't um we don't restart. And if it's moderate, we suspend and repeat an MRI every month until until it's uh either stable or resolving, and we could restart. And those are the tricky conversations, right? To when to restart.

SPEAKER_01

Uh and most uh geriatricians and uh almost all primary care docs don't actually give these drugs. So at the time of referral to you, what do you like to have in hand?

SPEAKER_02

So many of these patients have been waiting for some time, right, to to come and see a specialist. So it's I think uh primary care and geriatricians have uh an important role to uh maybe start that process and and having, if if they can, right, I think an MRI, right? So definitely having an MRI within the last year. Um if if it's possible to do an APOE genotype, I think that's gonna be really helpful because we can talk about the possible risk from you know the medication. And uh if they had a cognitive screener, I think it's also very helpful for sure because that would naturally occur, right, for in an evaluation. Uh so the most common one that we used in clinic is either an MMSE, right, or a MOCA. And the trial didn't use MOCA, uh, but we still use it in clinic, right? And and because we're thinking about patients that have a mild uh disease, so they have to have certain score. Uh and if they have an MMSE of uh above 20 or 22, right, I think you know we can consider these patients for the MOCA. Um, it's a little bit unclear uh at uh all the UC system at UCLA at least we have a score of 17 or more. So if they already come with some of these tests done, uh and we can say, well, this patient is eligible or you know, you know, or or not. I know that not everybody has access perhaps to doing an amyloid bed or you know, spinal fluid. Now we do have uh blood-based biomarkers, uh, and if they have a positive test, right, that'd be also helpful.

SPEAKER_01

So uh I in an ideal circumstance, you you'd have everything ready to roll. You'd have the ApoE typing, uh, you'd have a cognitive examination, you would have uh a blood-based biomarker and an amyloid scan. That that would be the best thing.

SPEAKER_02

That would be the best. But that obviously that doesn't happen very often. Very often.

SPEAKER_01

Yeah, it's it's interesting because I think a lot of primary care um physicians and um even geriatricians don't know that much about the blood-based biomarkers, uh, but they also don't know how to order amyloid scans. They don't even know that they're available and and that Medicare will cover them.

SPEAKER_02

So I don't think it's you know, like if if they come without in I often see patients they don't have those tests, right? Like the amyloid pet. So we would just order it.

SPEAKER_01

And then uh you do evaluations of patients who were potentially eligible for these treatments, but sometimes you find things that that make them uh not candidates, no longer eligible. How do you tell them that?

SPEAKER_02

Right. So when um it kind of depends on the reason why they're not eligible, right? Sometimes actually patients come and they're already in a moderate stage, right? And and knowing that I can tell them that they're they wouldn't be, they wouldn't benefit from the medication. It would they would just be at risk of having some of these side effects. And you know, in terms of other reasons, like if we find uh uh MRI findings, for example, right? That um, and actually the reasons why we tend to say this patient is not eligible because of they found we found they have multiple microhemorrhages, right, or one micro micro hemorrhage, those are reasons that uh they would put them at risk of having the side effects, right? So there's always, you know, uh I would say a good reason to uh to let them know why is that we are recommending or not recommending something. And uh it also helps, although it varies by institution, that we have an internal protocol, right? And a protocol that will tell us, okay, these are the the right patients, and these are not the patients that we can they would benefit.

SPEAKER_01

And then uh let's say somebody clears all these hurdles and you you've gotten the uh the test that you need. Um what do you tell them to expect? Uh you know, so many patients come to me and they say, can we talk about what they want out of their care? I want to cure my Alzheimer's, is what they say. Um, here you you have a drug that actually takes out the the biological marker of the disease and and flushes it down the toilet. Um what what do you tell people in terms of what they can expect from these drugs?

SPEAKER_02

Well, I try to be um right honest about what we know from the clinical drugs that what these medications can do and also what they don't do, right? So it's uh it's a balance between having uh hope, right, for for the use of these treatments. And usually what I tell them is that uh there is a medication, right, that they will remove the amyloid from the brain, which is uh the first protein that accumulates in the brain and then uh tau accumulates. And because it's early in that disease uh that can help slow down the progression. Uh but because we are not targeting the other pathways uh that occur in Alzheimer's disease, it does not cure Alzheimer's. And then this is actually the one of the trickiest questions, right? So, how do we explain to patients like what the clinical trials uh found? So, in general, I would say that it's between a 20 and 30 percent uh that it's low, that decline. And what does that mean? It's it's hard, right? But in we can say that it's perhaps five to seven months behind on the disease progression. Sometimes I also try to explain that it's it's more likely that they will stay in their current stage the next year, um, because we also have some some data that indicates that. And that's why I was saying that the earliest that we treat these patients, the more benefit that they will they will get. And then I also manage the expectations about um the side effects that we just talked about.

SPEAKER_01

So when they asked you is you know that you're taking this bad protein out of my my body, won't my memory improve?

SPEAKER_02

Because uh it's it's not just that protein, right? So uh there is um a pathway in the disease, or that we think what happens in Alzheimer's, right? So first there's accumulation of amyloid, then there's accumulation of tau, and then the brain uh cells, the neurons will uh they will malfunction and die, right? So then then we see the shrinkage in the brain. So because we're not addressing these other things that already perhaps already happen, right? There's already tau. Uh there might be already uh there surely brain cells that are malfunctioning, we're we're not addressing that. So we're preventing from uh from things uh progressing.

SPEAKER_01

So it's more preventive, you're telling them it's more preventive than it is restorative in terms of yeah, that they would be gaining stuff. And how long these um uh uh side these um benefits uh last? I mean you were saying that it doesn't cure the disease because there are other things that are going on as well, and some damage has already occurred. But the the clinical trials are out there, they got uh FDA approval from that. How long does this effect last?

SPEAKER_02

Well, we have uh now data from three years. Uh so the first trials we had information of like the first 18 months. So we only knew what happened at the end of 18 months, right? Uh but now there's an open label uh extension for Lekanemav, and now three or yeah, 36 months later, we can see that actually even in continuing treatment with Lekanimav, uh these patients can continue to benefit because it sort of stops the amyloid from reaccumulating, and then actually they may um gain further uh slowing of their decline three years later. After that, we don't know, right? And that's in the case of Lekanemav. In the case of Donanemath, uh, because that that was a different way how they provided the medication, because they could stop the medication early, like at six or at twelve months. And even those patients that actually stopped the medication early, let's say six months, they continue to benefit you know, at the end, uh a year later.

SPEAKER_01

That was kind of leading to my next question is that um you know at the end of these studies, uh people could be on in an open label phase, but other people might elect not to, or that there might not be an open label phase. The people who had amyloid removed successfully and they're no longer on drug, does it just come back?

SPEAKER_02

It will come back, um, but you know, it will take probably a couple of years to come back, right?

SPEAKER_01

Resets the clock?

SPEAKER_02

Yes. That's what we say they're kind of behind uh when that's sort of what we expect that they're behind in their progression.

SPEAKER_01

And um you you mentioned a little bit about monitoring people with MRIs while they're on treatment. Uh other things do you monitor in addition? How do you repeat their amyloid scans and when? Um, there was there was some thought about if people aren't showing amyloid removal, you know, why continue the drug?

SPEAKER_02

So there, yeah, there's a lot of things to monitor. Um so definitely we monitor for ARIA with the MRIs. Um, but we also do routine uh checkups with patients, right, to make sure that they're you know they're not having other new symptoms. Uh we monitor them also when they're having the infusion and shortly after the infusion because they can develop uh infusion-related reaction. So that's one of the other side effects that can occur somewhere between 10 and 25 uh percent of patients, they can develop this. But with those, we they're usually mild uh to moderate, and often we can give them a pre medication. Um I wanted to mention that uh before I forget, um But the other thing to monitor is the uh an amyloid pet, right? We we need to check if the medication is um is actually helping.

SPEAKER_01

And how often do you do that?

SPEAKER_02

We do it uh at the year mark.

SPEAKER_01

At the one year mark.

SPEAKER_02

Yes.

SPEAKER_01

And what happens if if they they don't show clearing, at least some clearing of the amyloid?

SPEAKER_02

So because we can extend the treatment for 18 months, uh so the FDA approve approval for lecanemap is 18 months. So even if they uh show benefit or there's no amyloid at the year mark, we will continue the recommended 18 months. For the nanemap, uh we we can do the the uh amyloid pet. And if it's negative, we couldn't stop. And I had actually uh patients that have stopped at that uh at that time.

SPEAKER_01

And have you been able to follow them out to uh or is it still too early?

SPEAKER_02

We're kind of in the early phase of like some patients finishing. So we yeah, we need to follow them um over time.

SPEAKER_01

They get scared?

SPEAKER_02

I get scared.

SPEAKER_01

Do they get scared?

SPEAKER_02

Um I think that um there's probably a a natural feeling of like worrying when they hear the the side the possible side effects. Um and and each person is very different, right? Because some of them are more risk-averse than others.

SPEAKER_01

No, but when they go off the medicines.

SPEAKER_02

Oh. I mean, I think uh the patient I'm thinking about, you know, they're uh and their family were kind of relieved, right? That they're because it it requires a lot of um time on their part. They have to come to the infusion, right? They have to come to the visits for the MRI. So yeah, so I think um that patient was relieved, but maybe they're they do ask the question, will this come back? Right?

SPEAKER_01

And and uh so one of the things that's kind of new on the horizon, just recently approved by the FDA, are the subcutaneous. So uh have you had any experience with it? Do patients like it?

SPEAKER_02

Um because we're just having patients that are finishing treatment, um, I've had those conversations. And um, I don't have any patients yet on subcutaneous. Uh we talked about it, and actually they preferred to go to the infusion center because maybe they were familiar with it. They wanted to continue. Um, but uh um the family member was a little bit afraid of like the needle, so they they just wanted to stay in the at the infusion center to continue maintenance dosing.

unknown

How interesting.

SPEAKER_01

So, um what's the crystal ball look like? What do you think are gonna be the big things that are gonna be with the anti-amyloid therapy over the next two or three years?

SPEAKER_02

Yeah, two or three years, I or or maybe perhaps a little bit longer. What I'm very excited about is about uh learning of the ahead uh trial and the trial blazer for patients who have amyloid in the brain but have uh no symptoms, right? So that pre-symptomatic. Um and perhaps we uh we find that the treatment at that stage uh perhaps averts or really slows the you know the uh incidence of Alzheimer's disease, and perhaps we're gonna be out of jobs, and that would be good, good day.

SPEAKER_01

Yeah, so just to uh put another spin on this, uh, because uh these are very important clinical trials that are finishing up. They're all recruited, et cetera. And the first readouts may be later this year or 2027. But what um Dr. Sanchez Lopez was saying is that these are people who have biological evidence of the disease, they have markers that are positive, and have maintained their cognitive function. So they're cognitively unimpaired. So this is truly prevention.

unknown

Right.

SPEAKER_01

This is whether you can interrupt the disease and prevent the development of mild cognitive impairment or dementia. And um it it's very it's very it's one of these things that keeps me up at night too, thinking about what the possibilities are.

SPEAKER_02

It's very exciting. Yeah, I'm I'm actually, yeah, like I said, looking forward to uh looking at those results, and I do hope that we find uh positive results.

SPEAKER_01

Thank you. Uh I've learned a lot, and I'm certain uh that others have. And if if you want to learn more, please come to the Intensive course in September. Um there will be this material will be covered as well as new.