The Earliest Clues: How Genetic Populations Illuminate the Path to Alzheimer’s Prevention
Welcome to the Alzheimer's Research Podcast, a show reshaping and leading the conversation around Alzheimer's prevention, brought to you by the Alzheimer's Therapeutic Research Institute at Keck School of Medicine of USC. Whether you're a clinician, a researcher, or someone who wants to change their mind, these conversations explore the possibilities within reach to prevent and effectively treat Alzheimer's disease. I'm your host, Shelley Moore.
Mickenzie Vought:And I'm your cohost, Mickenzie Vought
Shelley Moore:I'm so excited for today's interview. We are sitting down with Doctor Michael Rafii, who's the medical director of the Alzheimer's Therapeutic Research Institute. He's a professor of Clinical Neurology at the Keck School of Medicine. He also leads the amazing Alzheimer's Clinical Trial Consortium for Downs syndrome.
Shelley Moore:We're really going to focus on what we're learning from this group, why they're so important to the field, and really how they are the heroes. And you'll understand the double meaning of that in our talk today.
Mickenzie Vought:Yeah, I felt so fortunate to get, a perspective from Doctor Rafii of the work that he's doing specifically with adults with Down syndrome, and the prevalence within that community for Alzheimer's. And so he brought so much hope so much knowledge to the conversation. And he communicated in a way that I know you're going to
Shelley Moore:be able to follow and feel really connected to the work he's doing. So let's jump in. Hello, Doctor Rafii. We are so excited to sit down with you today and talk about the many, many hats that you wear.
Shelley Moore:And we're so grateful. I think to get us started, we'd really like to provide an overview of your unique role at ATRI, and then also your unique role in Alzheimer's clinical trials. If you could share that with us.
Dr. Michael Rafii:Sure. Well, it's a pleasure to be here. I'm the medical director at ATRI, and so what I do is I oversee the medical safety team. And the medical safety team is comprised of about 50 people. We have five medical monitors and about 45 clinical monitors.
Dr. Michael Rafii:And the medical monitors are responsible for the oversight of safety of our participants in our trials. They review all the adverse events, all the labs, EKGs, MRIs, to make sure that the participants in our studies are safe. Our participants will be in a trial that may last a year, two years, four years. And during that time, lots of things happen medically. So we want to make sure they're eligible and that they're safe during the course of this study.
Dr. Michael Rafii:We have five medical monitors, five physicians, and we're very busy. We have a whole portfolio of trials. So they're reviewing things all the time. The clinical monitors on the other hand are a group of individuals that are overseeing the conduct of our studies at all of our sites. So our clinical monitors go to every site on-site, in person, and review the documentation, review the processes, review the consent forms, and ensure that the study is being conducted in the right way.
Dr. Michael Rafii:They meet with the team at the site, they answer questions so that they ensure that the sites are following the protocol accurately, correctly, which is also critical for the safety of our participants and the integrity of the trial. The goal of the medical safety team is not just to ensure that the participants are safe in that regard, but also that the data that's being collected and presented to an independent safety monitoring board to review the safety of the studies, that that data is also of, you know, the greatest accuracy. So every several months, there is a team of independent physicians that review all of our trials to make sure from a, 30,000 foot view that the participants in those trials are safe and there are no safety signals. And so with all of that effort, we ensure that when a participant enrolls in our trial, that they're eligible and that they're being monitored very closely for the duration of the study.
Shelley Moore:How did you first get into this field of work and where did you start?
Dr. Michael Rafii:Well, I, I've been working with Paul Eisen and this group for about seventeen years. I was really interested in Alzheimer's disease, or became interested in Alzheimer's disease in college. The first time actually that I met with one of the researchers, he had me go into a clinical exam room. He was a neurologist at an ADRC. And he interviewed this woman who was in her 70s and very forgetful.
Dr. Michael Rafii:I had never seen anybody with Alzheimer's disease before. And he proceeded to do a spinal tap after the interview. And he collected the spinal fluid, and again, I'd never seen that before. And he handed me the tube and he said, you know, Mike, we're going to try to understand this patient's forgetfulness with analyzing this fluid. And, that was, you know, really interesting.
Dr. Michael Rafii:And then my job was to take that sample to a lab across the campus where there was a team of researchers who were going to be analyzing that fluid. It was fascinating to me, that process, and to see what they were doing. And that experience, one of, one part of it was that I got to present my own work at a conference in 1993 in Washington, DC for the Society for Neuroscience. And in this, conference, there were 20,000 researchers presenting on the brain and their research. And it was just an electrifying experience for me, again, having never seen anything like this.
Dr. Michael Rafii:And I was, I was hooked on that sort of that excitement and the thrill of discovery. I was actually in the room when the sky Alan Roses presented on the discovery of a gene that is called APOE4, and they thought was involved in Alzheimer's disease. And to witness that debate, you know, again, very, very inspiring for me. So, I went through and buckled down and studied hard and went to an MD PhD program and did my PhD, also on aspects of Alzheimer's disease, followed by internship and residency in neurology. And then from there did a fellowship with the late Leon Thal who passed away about six months after I arrived to work with him.
Dr. Michael Rafii:But when he passed away, they brought in several people, one of whom was Paul Eisen, and I started working with Paul and the group. And my aim has always been to, again, you know, that, that patient that I saw as a college student who was forgetful and trying to understand how this occurs, that's been really a puzzle that is facing our country, is facing thousands of researchers. And I find it, you know, just absolutely fascinating. One of my own interests has been translational research. And when I was a resident at Hopkins, it was a time when multiple sclerosis was getting conquered.
Dr. Michael Rafii:So I saw as a resident, the new treatments coming out for MS, which were antibody treatments. And at that time, MRI was becoming widely used, brain MRI to see strokes. We now had a treatment for stroke called tPA, which again, as a resident, I was able to administer. And in MS, there were plaques on MRIs. These are demyelinating plaques, but the MRI allowed us to see the disease.
Dr. Michael Rafii:And so clinical trials used MRI outcome measures for these developments of these new treatments. And when I was a resident, it became very clear that the field of Alzheimer's was undergoing the same changes. And I did a research project as a resident where I worked on PIB, which is Pittsburgh compound B, which was the first tracer that allows us to see amyloid plaques.
Mickenzie Vought:It's so cool that you can pinpoint to this moment as a college student and making that connection to a single face and a person who's got forgetfulness and how do we connect it into their spinal fluid, I just was really drawn by that. And I imagine that's something that you've returned to a lot. And it was really interesting in the scope of the interview that we had with Paul Aysen, where he talked a lot about the methods for identifying those that have Alzheimer's have gone from postmortem to doing a PET scan to doing that spinal fluid to now having a blood test. So seeing that all the way through, I love that you've got markers to be able to see that
Shelley Moore:throughout everything. That's so fascinating. I was just wanting to make sure the audience was understood how you see it. And when you say tracer, what, what does that mean? How does that work?
Dr. Michael Rafii:Yeah, so for, for any disease, our ability to measure something that's associated with it, and maybe even causative, is critical for developing a treatment. I mean, certainly making a diagnosis, but to develop a treatment. And so, as I was saying earlier, with multiple sclerosis, there are these demyelinating plaques that you can see on an MRI. And so clinical trials tested drugs that would make those plaques go away. And I remember as a resident where there were debates about, well, if you're making a change on the MRI, does that really have a clinical benefit?
Dr. Michael Rafii:And we're having the same debates today where we can see amyloid plaques in the brain with PET scans. And there were debates about whether removing the plaques has clinical meaningfulness. Nonetheless, being able to see what we think is part of the disease is critical, not just for diagnosing it, not just for understanding its natural trajectory, but also to intervene with different potential treatments and see if they work. In my mind, amyloid PET scanning revolutionized our field because we're able to now see those plaques and based on whatever treatment is tested, see if it has an effect. And now we've had several trials that have shown clearly removal of the plaque slows down the progression in Alzheimer's disease dementia.
Dr. Michael Rafii:And our field is now at a point where not only can we visualize plaques on a PET scan, but we can actually measure their presence in the brain through a blood test. And the blood tests now reflect what's happening in the brain. And that's, that's again, another major advance that we'll be entering into clinical practice as we move forward with new treatments.
Shelley Moore:So when we talk about a lot of your work with the cross section of clinical trials and, your commitment to people with Down syndrome. Can you talk a little bit about that work and what the consortium is that you are leading?
Dr. Michael Rafii:Sure. So when I was a junior faculty member, one of my interests was to develop not only an understanding of how to do AD clinical trials, but to conduct them and then to develop my own research program. I think every researcher hopes to have a set of hypotheses that they can test in their own line of research. And my interest in Down syndrome came from several different avenues. One of which was seeing adults with Down syndrome in my memory disorders clinic, and realizing that these individuals are developing Alzheimer's dementia at a very high rate.
Dr. Michael Rafii:My interest in imaging and using PIB in the past, led me to propose a small study to do PIB imaging in adults with Down syndrome. And from that experience, you know, applying for, small grants and developing, sort of an ADNI for Down syndrome. So for viewers who may not be familiar, ADNI is a very famous study in Alzheimer's disease called the Alzheimer's disease neuroimaging initiative. And it's really a study that follows individuals in the general population that has shown us how you have amyloid plaques in the brain decades before you develop any symptoms. And so to me, it seemed like we should have an ADNI for people with Down syndrome.
Dr. Michael Rafii:And I obtained funding to do a small study of understanding sort of can people with Down syndrome even get PET scans? Can they do MRIs? Can we measure cognition in somebody with intellectual disability that's related to their Alzheimer's disease and not necessarily to their baseline intellectual disability related to Down syndrome? And so, we launched a very small study called the Down Syndrome Biomarker Initiative. And that was really a pilot study that has now led to the Alzheimer's Biomarker Consortium for Down syndrome, which is a large multicenter study.
Dr. Michael Rafii:We are collaborators on that study. It's led by four investigators as multi PIs, but it really is replicating ADNI in this population. And my interest has been to use the data from this ABCDS dataset to try to design trials just like we're doing trials in the AD population. And about seven years ago now, we submitted an application to leverage the ACTC infrastructure of the coordinating center for ACTC, which includes teams that know about MRIs and PET scans, cognitive measures, monitoring sites, medical safety, statistics, all of these different elements that are needed to conduct clinical trials to leverage that infrastructure to run trials that are specifically designed for people with Down syndrome. And so we were funded and launched ACTC DS, which is basically ACTC for people with Down syndrome.
Dr. Michael Rafii:And we have over 20 sites around the world. Our first project that was funded was the trial ready cohort for Down syndrome. And that was something that was born out of my experience in having run two other trials in Down syndrome and realizing that people with Down syndrome don't necessarily have the same access to the latest healthcare for their general medical conditions. And so oftentimes when they come in interested in participating in research, we may find that they have undiagnosed conditions that would preclude them from getting involved in research. Someone who gets into research needs to be, you know, medically stable.
Dr. Michael Rafii:Their medications need to be stable. We really want to understand sort of the natural trajectory of Alzheimer's disease and not have other medical conditions that could interfere with our ability to assess that. And so the trial ready cohort was funded to enroll 120 people with Down syndrome, to make sure that they are stable, medically stable. They understand what research entails and are interested in getting involved in clinical trials when they become available.
Mickenzie Vought:So they're kind of like a precursor to being ready to do that when the trial
Dr. Michael Rafii:That's right. Are a trial ready cohort. They're individuals who've said, I'm interested and they get to know the site. The site gets to know them and they obtain MRIs and PET scans, blood tests, cognitive measures, as sort of background information before the trial actually launches. So we were funded to enroll 120 participants and we've had so much interest.
Dr. Michael Rafii:We're now over three fifty participants and, have gained additional funding to support this. We also work very closely with that ABCDS consortium and allow co enrollment of participants in both of those studies and have been working to bring trials to this cohort. So last year we launched in collaboration with AC immune, the ABAPE trial, which is testing a vaccine against amyloid. That's a very exciting trial. It's actually a follow-up trial to one that we had conducted earlier.
Dr. Michael Rafii:Very excited about this study because a vaccine, you know, it's very easy to administer and vaccines have helped save the lives of people with Down syndrome during the COVID pandemic. There was a great, uptake of vaccinations against COVID and it had a very positive efficacy. The second trial, which we just launched in conjunction with Ionis, is called the HERO trial. And the HERO trial is testing a treatment that goes after the amyloid precursor protein gene in people with Down syndrome. We know that people with Down syndrome have a higher risk of getting Alzheimer's disease because they have an extra copy of chromosome 21.
Dr. Michael Rafii:And on chromosome 21 resides the gene for amyloid precursor protein. So by having that extra copy of the APP gene, people with Down syndrome, have a very high risk of developing Alzheimer's dementia at a young age. Their average age of diagnosis of dementia is 55.
Mickenzie Vought:And what's the age of the general population?
Dr. Michael Rafii:About 75. So it's about twenty years earlier. And by the age of 40, almost all people with Down syndrome have those amyloid plaques, which is what, you know, we have shown in the Down syndrome biomarker initiative as a pilot study, but now it's been replicated in many, many other studies, including ABCDS. So the IONIS trial, HERO trial is targeting that APP and knocking it down. So even though they have an extra copy of APP, let's make it as if they don't.
Dr. Michael Rafii:And there are actually two cases of individuals with Down syndrome who are partial trisomies, meaning that they have the extra copy of chromosome 21, but they don't have the full copy of 21, and they're missing that extra copy of APP. And so they only have two copies of APP, and those individuals did not develop plaques and did not develop dementia. So we know from a genetic standpoint that extra copy of APP drives Alzheimer's disease in people with Down syndrome. And the HERO trial is trying to do just that. The third trial, which we'll be launching later this year, is the Aladdin trial.
Dr. Michael Rafii:And the Aladdin trial is going to be testing a drug donanemab, which is already approved in the general population. And, you know, people with Down syndrome, as I mentioned earlier, have such a high risk of getting Alzheimer's disease, but they're not being treated with donanemab or lecanemab, these new treatments that have been FDA approved, simply because there's no experience with these treatments. So we're running the Aladdin trial with a modified dose titration, with a lot of MRI monitoring to ensure that there's safety monitoring so that we can hopefully bring this treatment that's now approved for the general population to the Down syndrome population. And I would be thrilled if we could have such a thing, having had a clinic where adults with Down syndrome, you can see the onset of Alzheimer's disease, and, you know, just like the general population not having much to offer, this would be just fabulous, and I'm very excited about that.
Shelley Moore:And so because of the, this population's genetic risk, how does that inform the other populations? How rare is it to have genetics in the general population that are tied to disease compared to people with Down syndrome?
Dr. Michael Rafii:Yeah, great question. So about one percent of all Alzheimer's disease in the world is due to genetic causes, meaning that a genetic mutation, and we call this familial Alzheimer's disease or autosomal dominant Alzheimer's disease. These individuals do get Alzheimer's dementia at a very young age. There's almost always a family history of a parent who had early onset Alzheimer's disease, which is defined as someone having dementia younger than age 65. The autosomal dominant forms of Alzheimer's disease, there's one form that I'll mention, which is individuals who have a mutation in that APP gene, where instead of having two copies, they have a third copy.
Dr. Michael Rafii:So they are like the individuals with Down syndrome who have that extra copy of APP. These individuals who have an extra copy of APP due to a mutation develop early onset AD. And there are only a few thousand individuals with autosomal dominant AD in The United States. There are about five million individuals with Down syndrome in the world. And so it's a very large number.
Dr. Michael Rafii:It's equal to the number of Alzheimer's cases in The United States. It's a very large genetic population. And in my mind, this population, we've now seen that the rate of Alzheimer's disease progression is a bit faster and the biomarkers behave exactly the same way, almost exactly the same as they do in the general population. So we understand now since the past ten years, we have a better sense of how does Alzheimer's disease present in someone with Down syndrome and what is its course. And we now know that the number one cause of death in adults with Down syndrome over age 35 is Alzheimer's disease.
Dr. Michael Rafii:So although there have been huge strides made in prolonging the life expectancy of people with Down syndrome with better access to healthcare, we're now seeing that Alzheimer's disease is, is not allowing that to continue to increase so that the, the lifespan is now, seems to be stifled because of the presence of Alzheimer's disease.
Mickenzie Vought:Wow, that is shocking. And I'm interested with this particular population, with adults with Down syndrome, what are some of the barriers to research? Think as you were talking through like one, there's a need here, but to the access to precursor or other medical interventions that would make them viable for research is obviously lacking as well. But then what are some of the other barriers? And how has your team been able to overcome them or create, a system in which they can walk into these trials, and move this research forward?
Dr. Michael Rafii:Great question. So let me start by saying that, in 2018, after a lot of lobbying by advocacy groups, and in fact, an individual with Down syndrome who's a self advocate going to Congress and testifying on the need to better understand Down syndrome, affiliated or associated conditions to improve the lives of people with Down syndrome, there was a major change in policy. And that was the beginning of the INCLUD initiative. And the INCLUD initiative is a trans NIH program that is bringing research funding to understand Down syndrome in the fullest sense, not just Alzheimer's disease in people with Down syndrome, but also aging in people with Down syndrome, and some of the other associated conditions that we see in people with Down syndrome, and to include them in the various research programs that are taking place across the NIH. So this inclusion is the name of the program, INCLUDE, is bringing research funding to research programs to add cohorts and individuals with Down syndrome into existing programs.
Dr. Michael Rafii:So ACTC studying Alzheimer's disease and being the leading trials group for AD in this country, it just makes perfect sense that ACTCDS would leverage that infrastructure and bring that infrastructure to the service of people with Down syndrome. Now, to answer your question directly, how have we overcome some of those challenges or what are the challenges in the first place? It's a question of people with Down syndrome having access to clinicians who are expert in the various conditions that impact the life of someone with Down syndrome. So people with Down syndrome have a high prevalence of sleep apnea. There's a high prevalence of leukemia, childhood leukemia.
Dr. Michael Rafii:There's a lower incidence of solid tumor cancers. These are things that we really don't understand why it's occurring and need research to understand to get better diagnoses and potential treatments. One example of this is someone that I work with at USC, Doctor. Jonathan Santoro. I'm his K23 NIH mentor.
Dr. Michael Rafii:He has a K23 grant. He's a child neurologist at Children's Hospital of LA, and he has been studying Down syndrome regression disorder. And Down syndrome regression disorder is individuals with Down syndrome who are in their teenage years and in their early 20s who develop psychiatric symptoms. And these can be quite severe where they lose some of their abilities. And sometimes they develop catatonia where they're really not moving or speaking.
Dr. Michael Rafii:And this is obviously a catastrophic diagnosis. But what Doctor Santoro has done is look at spinal fluid and biomarkers on MRI, and he has found that there are some autoimmune aspects to this Down syndrome regression disorder and is running trials with treatments such as IVIG, which is an immune treatment to try to that turn overactive immune system. And he's seeing benefits in these patients and the trials are ongoing. So that's another benefit of the Include initiative.
Dr. Michael Rafii:But, you know, there are so few clinics around the country, such as Doctor Santoro's that specialize in adults with Down syndrome or kids with Down syndrome to bring the latest diagnostics. And I think that's one of the main challenges is access to specialists is probably the number one challenge. And then beyond that is to have trust in the provider and to know the provider and have the provider know them. I think that's where a lot of strides can be made in bringing the latest diagnostics and latest treatments, to this population.
Dr. Michael Rafii:A few years ago, the Global Down Syndrome Foundation, which is a very large advocacy group, published clinical care guidelines for adults with Down syndrome so that primary care physicians who may not see a lot of adults with Down syndrome would have a checklist of what they should be looking for and how to manage them. And I think that's been a great tool to help, again, empower clinicians to be able to help adults with Down syndrome. And again, to have awareness of these potential, you know, co occurring conditions and potential research that may go to help them.
Shelley Moore:So you mentioned this doctorate at USC, but you also have, you know, a role in educating the next generation or working with other researchers. Explain to me how it works academically and public private partnerships that you work on that are really helping you address the science in the Yeah.
Dr. Michael Rafii:So I feel very fortunate in through my training, at Brown and at Hopkins and working with people who are really very inspiring and just the best in their field. Having had been a resident myself to now train a generation, of neurologists, future neurologists, it was terrific. I actually published two books that are used by medical students, and another book by neurology residents in training for their board exams. And they're very widely used, and I'm very proud of having been part of that, process. In academic medicine, you know, it's a, there are three pillars, right?
Dr. Michael Rafii:There's research, there's education, and then there's clinical work. And it's hard to do all three, you know, at the same time, obviously. To have, even during different phases of your career, some elements where you can do that, think is very gratifying. So for me, having been involved in training residents and medical students, in terms of the research, public private partnerships are a key part of what we do. So obviously we rely on the NIH for funding.
Dr. Michael Rafii:I sit on an NIH study section where we review grants and I see how hard it is to obtain grant funding and how much competition there is and all the feedback that comes from experts to, you know, improve grants, and sort of the way that we do research in The United States. But I will say that public private partnerships, particularly in clinical trials are really critical. When I was starting in the Down syndrome field in 2012, people in the research field, including pharmaceutical firms, did not really think that people with Down syndrome could be in clinical trials. Would they be able to participate for a year long study or a two year long study? And it was a challenge to show, no, I think they can.
Dr. Michael Rafii:And and they can, and we've shown that. And by working with companies and helping them see the data and the quality of the data and the motivation of this community and this population helps them feel comfortable bringing their assets and their investments into this space. And so for me, you know, having seen no trials ten years ago to now having three at the same time ongoing with plans for more is terrific. It's a partnership with researchers, clinicians, and most importantly, the advocacy groups and the community, because without them, we wouldn't be able to do any of this. You know, it's a difference than the general population.
Dr. Michael Rafii:You know, the general population has so many more resources. Whereas in this Down syndrome population, it's a very unique population, it's a vulnerable population. Whatever we do, we want to do it right and we want it to be done properly and safely. But having collaboration with biotech companies and pharma has really helped move this field forward.
Shelley Moore:So if there's one thing you could tell somebody who has no idea about the field or the work, what's most important message you would want somebody to really understand about your work?
Dr. Michael Rafii:The mission of ATRI is to help bring the best treatments such that we can prevent Alzheimer's dementia.
Shelley Moore:Yeah.
Dr. Michael Rafii:Having seen patients obviously in the clinic, it's an awful, awful disease. And to not have much to offer as a physician is an awful feeling. I've, you know, seeing stroke patients and having the treatments that are available for stroke and multiple sclerosis and the amazing treatments that are available for MS, how can we get there so that we can prevent this terrible condition? And prevention is really, in my mind, the ultimate in ideal medical care, prevention. And to prevent, you really need to understand where the disease begin.
Dr. Michael Rafii:When does it begin? How does it begin? And so to understand a genetic population really lets you understand exactly when does the disease begin? When does Alzheimer's disease begin in a genetic population? And translate that to maybe that's the earliest, whatever biomarker that may be, is something that we can use in the general population to find the absolute earliest.
Dr. Michael Rafii:Because earlier you intervene, the greater your chances are of success. So what I would want to convey to someone who's trying to understand our field and our mission, it's, we know what we want to achieve. We want to achieve prevention of dementia, but to get there, there are so many steps that are necessary. And the very first step is to understand the beginnings of the disease, then to validate biomarkers of it, to validate biomarkers that can be used for diagnosis, can be used as outcome measures and trials, then to design trials, to find treatments, to bring those treatments into a clinical trial, run the clinical trial, meaning recruit for it, enroll participants, collect the data, clean the data, lock the data, present the data, and then to look at it and see what's the next step, and to share the data. That, that's kind of the mission of ATRI.
Dr. Michael Rafii:And it's a very long process, but here we're able to deliver on all of that. We're able to use studies like, ADNI to, and LEADS, which is another study looking at early onset AD, to observe the natural history of Alzheimer's disease, and then to take those learnings and design the best trials to bring these latest treatments, the newest treatments to this population. And we're replicating that in the Down syndrome population. I'm very proud of that.
Shelley Moore:As ATRI is celebrating ten years, but of course you've been at this much longer. What are your hopes for the future of Alzheimer's research and what are you most excited about?
Dr. Michael Rafii:Oh, well, I'm very excited. One of the roles I have is I'm Co PI of ALSNet. This is the Alzheimer's Association Alzheimer's Network for Diagnostics and Treatments, and it's a registry. Every patient in The United States who gets treated with these new, monoclonal antibodies, lecanumab and donanemab, but also brexipeprazole, which is a treatment for some of the, behavioral issues in Alzheimer's disease. These new treatments, these individuals go onto a registry and the registry is actually used to help for Medicare coverage of these treatments, but also helps us collect real world data on how these treatments are going in real patients, in clinics around the country.
Dr. Michael Rafii:And so Alzanet has been in my mind, a view into the future, a perspective into how will not just the current treatments, but the next generation of treatments be rolled out. And I can tell you that the challenges that I see and the things that I'm very excited about to tackle are things like diagnostics. Can we use blood tests as a screen to identify someone who may have elevated brain amyloid, who's perfectly asymptomatic and maybe, you know, 55 or 60 years old and otherwise fine. And if we see it, then triggering them to have a further evaluation done, maybe a PET scan, maybe a spinal tap, maybe cognitive testing. And should that come back positive to then tailor a treatment that's appropriate for their stage in Alzheimer's disease and the continuum of Alzheimer's disease.
Dr. Michael Rafii:Right now, we have these treatments available for early AD, but I'm hoping in a few years we'll have treatments available for the prevention of AD dementia, preclinical AD. And I think that that's sort of the next step earlier in the disease.
Mickenzie Vought:Yeah, extending the runway on that. That's so fascinating. I
Shelley Moore:wanted to just circle back really one question, that I have about the HERO study. And if you could just describe what the intervention is that you're testing. So I understand it in the scope of like everything in terms of what we know about the amyloid cascade and tau, what is that treatment and why was that selected?
Dr. Michael Rafii:Yes, thank you for that. So just to be clear, the ABAPE trial is testing a vaccine against beta amyloid. And the Aladdin trial is testing donanemab, which is a monoclonal antibody against beta amyloid. The HERO trial is testing a treatment called an antisense oligonucleotide. And what this is, is a, it's a segment of RNA, if you will, which if you remember that in biology, genes go from DNA to RNA to protein.
Dr. Michael Rafii:And so APP, amyloid precursor protein, starts as a gene. It then gets transcribed into RNA, and then that RNA gets translated into a protein. And what I've been saying is that that extra copy of APP causes an extra copy of the mRNA, of the RNA, for APP to be created. And then that extra copy of the APP RNA gets translated into extra APP protein. And that APP protein, when it's in excess, leads to formation of beta amyloid because APP gets cleaved to form beta amyloid.
Dr. Michael Rafii:So the treatment for the HERO trial is targeting that APP RNA and inhibiting it. It's not shutting it off completely. It's just normalizing it from the three copies down to the two copies, to the amount that would be equal to that. So the treatment for the HERO trial is an antisense oligonucleotide. And each of these treatments are delivered differently.
Dr. Michael Rafii:The vaccine is an injection. The donanemab is an intravenous infusion. And for the ASO in the HERO trial, it's actually an intrathecal treatment. So it's like a lumbar puncture that's injected into the spinal fluid. Now that sounds, you know, pretty invasive, but in fact, are 14 treatments that are FDA approved that utilize this type of approach and therefore genetic conditions.
Dr. Michael Rafii:So, you know, when you're facing an illness like Alzheimer's disease, there are different ways to approach it. LPs have been done for over one hundred and fifty years. They're part of, you know, medical practice. And so although it sounds invasive, it's actually pretty routine.
Shelley Moore:Thanks for clarifying, because I think it's interesting to understand the different approaches.
Mickenzie Vought:Just hearing you explain that in such plain terms, I was able to follow it. And I imagine one working with people with Down syndrome, and their caregivers, it's important to bring some peace and presence to the conversation. And so it's not so scary. And it doesn't feel like you can't approach it, and that they're included in this research. And so I think I was really fascinated and really, really encouraged that I was able to follow and you have a great way of breaking it down in simplified terms to make it feel less scary.
Mickenzie Vought:And I wondered if that played a role in what I know is that you've been involved in a couple of really unique film and television projects and opportunities. And I would make up that it's because you have such an ability to communicate these difficult ideas in a simplistic way. So would you tell us a little bit about that as we round out our interview?
Dr. Michael Rafii:Sure, sure. Thank you for that. That's a very kind compliment. Before I do that, I just want to mention that this language, that we use and, and having it be, you know, clear and concise and appropriate for people with Down syndrome is that as part of ACTCDS, one of the things we did is we put together an advisory board comprised of people with Down syndrome and their loved ones. And this is what we're doing in the ACTC with the general population.
Dr. Michael Rafii:These are individuals who are self advocates who are reviewing, they're reviewing our protocols. They're reviewing our consent forms. They're reviewing our messaging, and they're giving us feedback on are the pictures appropriate? Is the wording appropriate? Is there any place where we could be more clear talking about the risks and the benefits and all the procedures that are involved?
Dr. Michael Rafii:And that's been a wonderful addition to our work to bring understanding of what we're doing to this, to this community and to this population.
Mickenzie Vought:We had a fascinating conversation with Sarah and she was able to articulate how we're doing with the general population. And I love that you guys have started a board on this side too, advisory board.
Dr. Michael Rafii:Yes. And, and that's in the spirit of the INCLUD initiative, right, is to take what works in an NIH funded program and to modify it to improve the lives of people with Down syndrome. And that, that advisory board, which actually is an advisory board to ACTCDS, but also ABCDS, and that's a shared group, It's been terrific. To answer your question about the other work, when you are producing a film or a television program, and you want to ensure its accuracy for the public, How do you go about doing that? And what USC has done is said, we will allow our faculty who may be experts in physics or economics or Alzheimer's disease to spend some time with you and talk about your script and provide you some feedback.
Dr. Michael Rafii:And so for me, over the years, I've had an opportunity to work with several shows about improving accuracy. And to me, I've actually been blown away by how seriously the writers take the content and the accuracy of the content. And that's been also very gratifying in working with people like that from so much, such a different background, but with the same purpose in mind.
Shelley Moore:Yeah. I love the characters you've been able to create with shows like This Is Us. And and then, of course, the the more documentary style, you know, telling the stories where you've had deep connections such as remembering Gene Wilder. And I hope that we get to tell some stories in the future about for survivors and about the future of being able to actually have prevented this disease. What are you most hopeful about?
Shelley Moore:What gives you the most hope every day?
Dr. Michael Rafii:Well, I think having folks in the community that realize how much work it takes and how long it takes for a treatment to become available. I think having that shared understanding is a great first step. And that means we need to be able to communicate and to use the same language and to be understandable and to be clear. I'm glad that we have this opportunity to speak today because I hope it gives a perspective of what we do, what we're doing, and what we're hoping to do as we bring new treatments for the prevention of Alzheimer's disease at ATRI.
Shelley Moore:And as we wrap up, is there a very specific call to action for your work that you would want to share with the audience?
Dr. Michael Rafii:Two. Number one is if you have a loved one who you see as having changes, there are so many reasons not to address it. But my recommendation is not to be afraid, is to have it evaluated, to have this checked out. And it's doing them a huge service. It's doing the loved ones, the family unit, huge service to understand, at least to understand what to expect at the very least, and potentially to get access to treatments, some of which are disease modifying treatments, some of which are symptomatic treatments, but just to have that awareness, to empower patients.
Dr. Michael Rafii:I think that that's really the first thing I would say is if you have a loved one and you see that there's some forgetfulness, it could be something as their thyroid hormone is in an abnormal range, or maybe they're taking a medication that has a side effect that's having them develop memory problems. The second recommendation is to be self advocates and to learn about what's going on. And this field is constantly changing, but there are great resources out there, including on the ATRI website to read about what are the new discoveries? What are the facts about amyloid? What are the facts about tau?
Dr. Michael Rafii:What are the facts about placebo controlled trials? And to weigh things that you may hear about, you know, supplements or certain exercises that may have huge efficacy, but in fact may not, and that you really want to go to a trusted source to get that information. So those would be my two recommendations.
Shelley Moore:Yes, and we wholeheartedly believe that the Alzheimer's Therapeutic Research Institute and our website at atri.usc.edu is the place to find trusted information in this field and this work. And you're a prime example of that, Doctor Rafii. So thank you so much for your invaluable time to sit down with us.
Dr. Michael Rafii:It's my pleasure.
