Clarifying the Alzheimer’s Disease Clinical Trials Landscape

Transcript

Intro: I'm Dr. Nathaniel Chin, and you're listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

ADRC Announcement by Alexia Spevacek: We interrupt today's episode with a word from the Wisconsin Alzheimer's Disease Research Center. On this podcast, we often discuss different factors that can lead to cognitive impairment or dementia. Both memory loss and hearing loss are sometimes perceived as normal signs of aging, but both can actually be deeper indicators of brain health. Have you ever wanted to dive deeper into the impact of hearing loss on the brain? Join the Wisconsin Alzheimer's Disease Research Center for the annual Fall Community Conversation happening Thursday, October 9th, 2025 from 4:30 to 7:30 p.m. Central time at the Middleton Performing Arts Center in Middleton, Wisconsin, and live streaming on our YouTube page. This year's Fall Community Conversation is focused on exploring the science behind hearing and memory loss and why it matters for brain health as well as empowering attendees to take steps to support their brain health. The event will feature a health and wellness resource fair, talks led by University of Wisconsin faculty and a Q&A with the evening's presenters. To learn more about the Fall Community Conversation and how to attend, go to adrc.wisc.edu/fcc2025. That's adrc.wisc.edu/fcc2025 or find the link in the episode description. Thanks, and we hope to see you at the 2025 Fall Community Conversation

Dr. Nathaniel Chin: Welcome back to Dementia Matters. Clinical trials for Alzheimer's disease treatments are instrumental in improving the quality of life for those diagnosed. With dozens of therapies and new approaches in development, the treatment landscape is always evolving and can be tough to follow. Thankfully, there are experts who dedicate their time to making it more accessible. Today, I'm joined by one such expert, Dr. Jonathan Graff-Radford. Dr. Graff-Radford is a behavioral neurologist and associate professor at Mayo Clinic in Rochester, Minnesota as well as co-investigator in the Mayo Clinic Alzheimer's Disease Research Center and the Mayo Clinic Study of Aging. He's also the vice chair for the Mayo Clinic Department of Neurology. At the 2025 Spring ADRC meeting held by the National Alzheimer's Coordinating Center this past May, Dr. Graff Radford presented a comprehensive overview of where Alzheimer's treatments stand now and where they're headed. Today he'll share some highlights from his presentation. Dr. Graff Radford, welcome to Dementia Matters.

Dr. Jonathan Graff-Radford: Thanks so much for having me here today.

Chin: To start, John, what got you started in Alzheimer's in the field in particular with clinical trials?

Graff-Radford: Well, I was always fascinated by the brain. In high school, I used to read books by Oliver Sacks, like The Man Who Mistook His Wife for a Hat had a big impression on me. It was always in the back of my head that neuroscience may be a focus for me. Then when I went to medical school, I had some great mentors. I got to work with Ken Heilman, who is a behavioral neurologist at University of Florida, and Michael Okun, who is a movement disorder neurologist, and they really inspired me to pursue the field.

Chin: What about clinical trials though? You could do a lot with behavioral neurology. Was there something in particular that drew you to that expertise?

Graff-Radford: During residency at Mayo, I got to work a lot with Dave Knopman, who is a clinical trialist here, and got to see the clinical trials that we were offering, meet with the participants. I was really inspired by the people participating in clinical trials, their altruism, as well as the family's commitment to try and find a cure for Alzheimer's disease and how important it was to them that we offer clinical trials. It really brought hope to a lot of them. I wanted to be part of that. I started to get involved initially as a co-investigator and then became a site PI for several clinical trials here.

Chin: Of course you're an active clinician, so you're seeing patients on a regular basis too. I'm sure that it is meaningful for you to be able to see them in clinic and then ideally have them in research too.

Graff-Radford: As a clinician, one of the common questions I get asked is “What's coming down the pipeline in terms of new trials?” It really is synergistic to be involved in both clinical care as well as clinical trials because you can give them an overview of trials that are ongoing as well as the ones that are going to be starting up in the next few years.

Chin: Funny enough, that's exactly what this podcast is, Jon. I'm glad we're sort of like your pseudo-patient here. Now you are involved in both the Mayo Clinic ADRC, which has a longitudinal observational cohort, and clinical trials, which as you just said incorporates interventions. How would you describe the difference between these types of studies to someone interested in just general Alzheimer's research?

Graff-Radford: Longitudinal studies like the ADRC follow participants over time to look at the natural disease progression and they don't intervene upon that disease progression. They're just trying to understand what are the risk factors for developing the disease as well as how that disease changes over time. In contrast, a clinical trial is really testing a specific intervention to see if that intervention helps that disease. Is it safe? They're really synergistic in our field. Observational studies provide really important knowledge about epidemiology and risk factors and trials are the ones that are bringing the new therapeutics to the clinic.

Chin: For our listeners considering participating in a clinical trial, what are key aspects of this type of research and participation that you think they should know about?

Graff-Radford: The first thing to know about is that it's voluntary. It's completely that participant's choice. You can decide whether you want to be part of the trial. You can leave the trial at any time once you've joined it. That's a really important first step to know about. Second is what to expect if you do a clinical trial. You may receive a new treatment, but you may also receive what a standard treatment in the field is or a placebo where you're getting a treatment that looks like the real treatment but it doesn't have the active ingredients. You want to know in the trial that you're enrolling in what that setup is. The second part is, what are the risks and benefits of participating in the trial? You want to understand if these are new therapies, what they are looking to do, as well as whether there have been any safety signals in prior trials that you should be aware of when enrolling in these studies.

Chin: This wasn't originally on one of my lists of questions for you, Jon, but since I have your time here, are you seeing more and more both patients asking or participants asking about this in the field in general, this concept of open-label extension? To me it seems like it's a way of helping with recruitment and retention, but also just from the clinical perspective, if something's proven in a trial to be effective, you as a participant really want to be on that. If you could just explain for our listeners open-label extension and then your perception of how it fits in the AD space.

Graff-Radford: An open-label extension is when a participant is done with the trial and they've gone into the trial, they've either received placebo or the study drug. After the study's done and their outcome is firmly established and the data's locked, there's an opportunity for participants to all get on study drugs. This is important for a lot of participants who feel strongly that they've given a lot to the trial and they want to make sure that they have an opportunity to be on that study drug, especially if it's promising. Certainly when there's a trial that's positive, that's particularly important to the study participants. It's something they're asking more and more about as we're starting up studies.

Chin: That kind of leads into my next question, which is asking about phase four studies and what that actually means. Before we get to that, can you describe the differences in the phases of clinical trials and what happens with drug approval after a Phase 3 study in particular?

Graff-Radford: It starts with a Phase 1 study. That's a smaller study. You're testing the safety and what dose may be appropriate for that drug to go on. You're also seeing how that drug interacts in the body. If that passes Phase 1, you'll move to a Phase 2 study. This is the study where you're starting to look at efficacy and side effects. You're also trying to get a sense of if the target is being engaged. If you're targeting amyloid in Alzheimer's disease, do we have an amyloid biomarker that's being moved by this drug? After that, those that are promising in Phase 2 move to Phase 3. This is really confirming the effectiveness in a larger population. This is what leads to regulatory approval. These are the large studies to show that there's a clinical efficacy. Often in Alzheimer's disease, you're looking for both a cognitive and functional scale that has been improved upon with a treatment. After that, there's a Phase 4 study as well, which is a post-approval study. That's where you're seeing how these drugs perform in the real world. How do they do once they're being used widely, not just in a restricted trial population? One of the things about clinical trials is they often have a selected healthy group of people with that condition. In the real world, we want to know are these effective and what's the safety signal as well. That comes after you get that approval.

Chin: Not every study has to do a Phase 4 though, right, Jon?

Graff-Radford: Correct. Yes.

Chin: Before you get to Phase 1, and I ask this because it just was asked of me by a patient, I think it's a great question. Before you get to Phase 1, is it safe to say most drugs, if not all of them, have been tested in animals prior to getting to phase one? Or what happens in that pre-Phase 1?

Graff-Radford: That's a common pathway to have animal studies showing that there's a mechanistic reason to move it into Phase 1, but there's occasionally studies where these are compounds that are already widely used and you're repurposing them. That wouldn't necessarily require a Phase 1. Sometimes there'll be supplements that are widely used and considered to be safe that are being studied. Those wouldn't necessarily have the same pathway.

Chin: With that in mind, I want to start asking a few questions about specific trials that have happened, are happening, or you think will happen. Given your expertise, I'm hoping you can share your interpretation and key findings you found from the two Phase 3trials related to amyloid removal, that being Clarity AD and TRAILBLAZER-ALZ 2. What do you think are the most relevant takeaways for our listeners?

Graff-Radford: Big picture takeaways–both trials showed that these monoclonal antibodies successfully remove amyloid. That’s clear. They also showed a slowing of cognitive and functional decline at 18 months. It was a slowing in the range of 25 to 30 percent. It's important to recognize that they don't stop the disease. They don't reverse the disease. It's a slowing of the decline. There's been some debate in the field of how relevant this 25 to 30 percent slowing is. I think if you think about it on the Clinical Dementia Rating Sum of Boxes (CDR-SB) scale that was used for Clarity AD, you could consider it clinically relevant for some patients who would want to remain at a more mild stage of the disease for a longer period of time. There are also some safety concerns that need to be raised. Both drugs cause what's called amyloid-related imaging abnormalities, or ARIA. There are two types. One is brain edema and the other is microbleeds or superficial siderosis, which are safety concerns that need to be monitored. Fortunately, these safety issues can be safely addressed with careful monitoring, and the FDA has recommended an MRI schedule to do so. We've treated almost 100 folks here and, with the safety regulations in place, we've had very good success with very little side effects.

Chin: Is there anything different that you want to mention about the TRAILBLAZER-ALZ 2, or do you consider those together?

Graff-Radford: I think they're different. Clarity, which tested lecanemab, one big difference is the frequency of dosing. Lecanemab is given every other week. Donanemab, which was in TRAILBLAZER-ALZ 2, is given monthly. From a dosing convenience standpoint, that's a difference for patients. There was also a difference in eligibility for the trials. Lecanemab required a positive amyloid biomarker with an amyloid PET. Donanemab used both an amyloid PET and a tau PET for inclusion criteria. When you're trying to compare their efficacy and side effects, you have to realize these are actually different study populations. It's hard to make a head-to-head comparison in terms of efficacy. I explain to my patients that we can't make that determination of which one may be more effective than the other. One of the things that did come up is that donanemab did have a higher rate of ARIA reported than lecanemab. One of the key parts about a new therapy is understanding if we can start to deliver these drugs more safely and effectively. Just this year, they published a study that if you do a modified titration of donanemab, where you give less of a dose with that initial dose but the same total amount in six months, you can decrease the ARIA rate from about 24 percent to 13 percent for ARIA-E, which is a pretty big difference. I think we're going to continue to see that the drugs can be delivered in a way that can be safer if we continue to learn from these follow-up studies.

Chin: You mentioned two things in your answer, Jon. Clinical meaningfulness–one, it's being debated, but it's important to be able to talk about that. Then two, time, that being a measure. You'd mentioned slowing over 18 months. I'm curious how you, in clinic, now explain that to a patient that has mild cognitive impairment that's thinking about whether they should go on this therapy. How do you explain the potential benefit? You've done a nice job of explaining the potential risk with ARIA, but how do you frame the potential benefit?

Graff-Radford: What I try and make sure they understand is that this is a slowing and not a stopping. I really try and convey that while we do want to maintain you at your current level, we're not going to expect improvement and we're not going to expect that the disease is going to stop. It will get worse over time. We're hoping with these drugs that we're slowing down how this will progress. On average, which is not the case for an individual patient, we're looking at a 30 percent slowing, which is annualized to about three to four months of relatively preserved cognition annually. For different people, that could be quite meaningful. For other people, particularly those where the infusions might be a hassle, they may decide if it's not a cure or a stopping of the disease, this isn't the drug for me. In fact, when we've reviewed people for safety and offered them the drugs, about 80 percent of people go on to start the drugs. That means about 20 percent of people here at our center are saying even though I'm eligible, based on the risk-benefit profile, these aren't the drugs for me.

Chin: Before we get into the prevention space, can you tell us a little bit about the two other anti-amyloid drugs being studied, remternetug and trontinemab?

Graff-Radford: Sure. Remternetug is given subcutaneously as an anti-amyloid drug. One of the concerns about the current drugs is that they're given by infusion so people have to go into infusion centers, which makes it challenging to scale them. Lecanemab, fortunately, was just approved for subcutaneous therapy for maintenance therapy just this last few weeks, which is a big step in the right direction to being able to treat more people. Remternetug is subcutaneous from the start, which is a key advantage. It's also thought to potentially have superior amyloid clearance and fewer reactions when they get the drug as well. It's being studied in a couple of studies. One is called TRAILRUNNER-ALZ 3, which is taking people with either no cognitive impairment yet but a positive amyloid biomarker or minimal cognitive impairment. They're letting in people who are on that threshold of mild cognitive impairment. It's looking at 18 months of home-administered therapy and looking at if you can delay the conversion to MCI on the CDR. That'll be an interesting study because it's going to look at a potentially safer, more effective anti-amyloid agent and also being able to deliver it in the house versus having to come into the clinic for it. Trontinemab is one my colleagues have gotten very excited about because of the neuroscience behind it. It uses what's been termed the brain shuttle to enhance blood-brain barrier crossing. They took gantenerumab, which was a monoclonal antibody that was not effective in clinical trials. It removed amyloid a little bit and did cause ARIA, but it didn't hit any of the clinical endpoints that lecanemab and donanemab hit. What they did was they fused gantenerumab with a fragment that binds to the transferrin receptor, and that allows it to cross the blood-brain barrier very effectively. It's getting into the brain at a much higher level. In the early studies, they've shown that it clears amyloid very fast and has minimal side effects. By minimal, I mean minimal ARIA, but minimal doesn't mean no ARIA. There was one case of someone who had baseline features of amyloid angiopathy, like superficial siderosis, who did die within the study. Even with these newer antibodies, we're going to have to be vigilant about monitoring and screening people for safety. It is an exciting one because of how quickly it removes amyloid and how few side effects have been seen so far.

Chin: That does sound very exciting. I want to move a little bit more into the prevention space. For our listeners, what should they know about the AHEAD study and then the TRAILBLAZER-ALZ 3 study? Just so you know, Jon, in your answer, Dr. Reisa Sperling has been on to talk about the AHEAD study, so you don't have to give us a lot of the background. For our listeners who haven't heard that, that episode will be in the show notes. Jon, what do you think they should know? Key takeaways from these two important prevention studies.

Graff-Radford: The AHEAD study, as you mentioned, Reisa Sperling is the PI of it, and it's testing whether we can remove amyloid before people have symptoms and potentially delay, or even prevent, Alzheimer's in some individuals. They had a very innovative screening technique using a blood biomarker. If that was positive, they got a PET scan to measure amyloid in their brain. It's testing to see if, once someone has a high amount of amyloid, can we remove it and delay or prevent clinical symptoms from occurring. The TRAILBLAZER-ALZ 3 is also a preclinical study but it's using donanemab, not lecanemab. It's designed a little bit differently. It's a decentralized design using remote cognitive screening and blood biomarker testing. It has a reduced participant burden, which is intriguing for those interested in being able to deploy these more widely in populations that normally wouldn't have access to them. It's also looking at whether removing amyloid at this early stage before symptoms develop can delay or prevent Alzheimer's disease symptoms. Both are very exciting, and by 2027 or 2028 hopefully they'll be wrapped up and we'll have that answer of early amyloid treatment for the field. There's a lot of people who feel that may be the best time to test amyloid removal more so than after people already have symptoms because, as people in the biomarker space know, people with mild cognitive impairment can have a lot of tau in their brain. Treating people at that earlier stage may be an ideal time for them to see if that works.

Chin: There's one other trial in the Alzheimer's space that I think made a lot of headlines, and that was related to brexpiprazole and the treatment of agitation associated with dementia. Can you tell us what exactly this drug is and what the study showed?

Graff-Radford: It's an atypical antipsychotic and it works on serotonin and dopamine receptors. This is really important for the Alzheimer's space because, as we've moved into these disease-modifying therapies, there's a lot of people with symptomatic Alzheimer's disease that have challenging symptoms and agitation is one of them. This drug was approved for agitation related to Alzheimer's dementia, and it showed a modest effect at decreasing agitation. It's a big deal for the Alzheimer's field because we haven't had many successes when it comes to neuropsychiatric symptoms in those trials. I think it's a step in the right direction, definitely more needs to be done. There are a couple of cautions. One is because it's an atypical antipsychotic, it comes with a black box warning, like all atypical antipsychotics in dementia, that in the elderly with dementia they're associated with an increased risk of death. It's thought to be cardiovascular typically. There should be some caution when prescribing it. It's important for us to talk about it because it is another recent success in therapeutics for Alzheimer's disease when we went about 20 years between the prior drugs and these anti-amyloid agents.

Chin: That's a pretty significant drought of success there, Jon. In my last section of questions, I'd love to hear a rundown of other studies that are happening or will happen in the near future that you find to be exciting.

Graff-Radford: One of the ones coming up this year that I think the field's very excited about are the EVOKE trials, and they are studying GLP-1 agonists in Alzheimer's disease. Many people have seen the trials of GLP-1 agonists for diabetes, for weight loss, for sleep apnea, for fatty liver disease, and they've consistently shown that they can improve diabetics' blood sugar, help people lose weight, and actually decrease sleep apnea. Now they're being studied in Alzheimer's disease, and there are a couple of mechanisms of action that people are interested in. One is they improve blood vessel health. If you lose weight and get your blood sugar under good control, you're going to have healthier blood vessels. The second is that they may have neuroinflammatory effects. The combination of those two may be very helpful in Alzheimer's disease. It's anticipated that later this year we're going to hear the results of that trial. The cool thing about these studies is they were done with an oral GLP-1 agonist. This would be something that's easily deliverable to folks compared to some of those infusions. I think that's one big one that we're waiting for. There are a couple other exciting trials I'll just mention. One are trials targeting tau. I mentioned–we've discussed amyloid for most of this podcast, but there are some interesting compounds in the tau pipeline. One of them is called BIIB080, and it's an intrathecally-delivered tau agent. It's given through the cerebrospinal fluid. It really targets the microtubule-associated protein tau and decreases its production. Cath Mummery, a few years ago, presented the initial data and showed that it can actually decrease tau PET signal, which is one of the few drugs we've seen that engages tau that strongly on a biomarker standpoint. It's now being tested in Phase 2 trials in Alzheimer's disease, in MCI and mild dementia. Even though it's challenging to administer, it's really important for the field because it's one of the first ones to show that degree of target engagement for tau. The other ones I'll mention quickly are happening in autosomal dominant Alzheimer's disease. These are people with the genetic mutations that run in families. The DIAN study is doing a combination therapy study where they're looking at combining anti-amyloid agents with anti-tau agents. That's an exciting place to be. They're using a tau agent called E2814, and they're looking at whether that additive effect of targeting two parts of the Alzheimer's disease cascade will be more effective. That's also happening within the Alzheimer's Tau Platform (ATP), where they're going to test several tau agents at the same time and see which one prevents tau uptake the most on PET scans and then move that one to Phase 3 so you can have a quicker turnaround for these trials. Those are the big ones that I'm very excited about, but there's lots more out there as well.

Chin: To end today, Jon, what are your key questions for the future of Alzheimer's treatments? What do clinical trials need to address given the recent successes that you've talked about?

Graff-Radford: One big thing is, how do we optimize the timing of combination therapies? Anti-amyloid and anti-tau agents are coming, but there are other combination therapies looking at inflammation as well. Who and when you should give these drugs is a really important question. We also need to continue to identify subgroups who might be responders to different treatments. We're already seeing that with the anti-amyloid agents that it appears people with a low amount of tau at baseline do best with these drugs. Can we continue to make these drugs safer? We already have some progress in that space. What are the long-term outcomes of these people? We only have 48-month data, but it's going to be important to continue to follow people who have been treated to see what happens to them. And then a big thing is, how do we address non-Alzheimer's disease co-pathologies like cerebrovascular disease and other comorbidities in trials? Are there any neuroprotective strategies that we can employ to enhance that disease modification?

Chin: With that, Jon, I'd really like to thank you for being on the podcast, going over this incredible overview on clinical trials. I certainly think we're going to have you back on to talk more about Alzheimer's research.

Graff-Radford: Thanks so much for having me.

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