Dr. Paul Aisen in Conversation on World Alzheimer's Day

On September 21, 2022 – World Alzheimer's Day – Dr. Aisen spoke with Angela An about the exciting developments in Alzheimer's Disease research. The two talked about some key updates in the research.

Dr. Aisen discussed the new ways in which drugs can be tested and evaluated. Just years ago, there were very few ways to see if drugs were effective; brain scans couldn't pick up on the microscopic changes and blood tests hadn't been developed yet. Now, however, scanning technology has improved dramatically where changes to the brain can be seen visually. In addition, blood tests can now detect if there is amyloid (an abnormal protein that builds up, causing AD) in the brain.

The two also discussed four exciting new drug candidates that are entering trials over the next 6 months. These new anti-amyloid drugs are unique in the ways in which they attack the amyloid and the ways in which they are administered. Dr. Aisen said, "We've never been in this position before with four therapies in late-stage testing. It is a tremendously exciting time." 

You can watch their conversation here, or you can read a transcript of it below.

Angela An: Last year was our inaugural world Alzheimer's Day chat where you and I joined again at an event like this and we talked about advancements, and if anyone can move the needle when it comes to Alzheimer's research it's you. Talk about the latest research that you are doing at ATRI.

Dr. Aisen: We want to develop effective treatments for Alzheimer's. We've been working on this terribly important problem for decades, and we are very excited about the progress that's been made. So we've learned much more about the disease than we ever understood before. We understand the biology of the disease. We have strong ideas on how we can interrupt the changes that cause memory loss in Alzheimer's disease, and a round of new therapies are now in the latest stage of testing. We really believe that we will see effective disease-slowing treatments available soon. So the first of a new class of drugs was given accelerated approval by the FDA. It's been controversial. The results of this particular drug have been somewhat murky. A whole bunch of follow-up drugs are coming through, and in fact, there are four drugs that are in late-stage trials that will be read out in the very near future, one of them any day now. A second one within a month and two more within the next six months. We've never been in this position before with four fascinating candidate therapies in late-stage testing that may be making it to the clinic soon. So it is tremendously exciting.

Angela An: That is exciting. Are you able to say what those drugs are because we are already getting some questions from people in the audience who want to know what are the medications and the therapeutics? Liz asked, what's worth trying for an 80-year-old person who has had Alzheimer's for a few years, and very little short-term memory?

Dr. Aisen: So Alzheimer's disease is a complicated disorder, but we're pretty confident that we know how it starts, and it starts with the accumulation of abnormal material in the brain that's called amyloid. Alzheimer's has two changes in the brain, plaques, and tangles, and the plaques are made up of a substance called amyloid, which is an abnormal protein, and we think that it's the amyloid that drives the process. And this first round of potential disease-slowing medications attacks the amyloid. And in fact, we know that they substantially clear amyloid from the brain, and we think that if we can intervene early enough, with the removal of amyloid from the brain, we can have a major impact on disease progression. So the four drugs that we'll be reading out over the next six months are what we call anti-amyloid drugs. Each of these is an antibody that's manufactured and then used as a treatment to attack the amyloid and remove it from the brain. Preliminary studies are encouraging, but as the disease progresses, it becomes more complicated with many abnormalities and in the later stages of Alzheimer's dementia, removing amyloid may not be particularly effective. So at the same time, we're working on medications for all stages of Alzheimer's, and with regard to a question about what can someone with symptoms of Alzheimer's dementia do now? There are drugs on the market that help, these are not disease-slowing medications, but rather medications that boost brain function that can, modestly, but hopefully alleviate memory impairment in people who have Alzheimer's disease dementia. I think those drugs can be helpful. We still have lots of work to do. We need very effective drugs for everyone. At any point in this disease. But we've made huge progress and so we are encouraged by these drugs that we'll be reading out in the coming months.

Angela An: I think that's important, Dr. Aisen that you noted that while some of those drugs may not quite slow the progression, they will treat the other symptoms, if you will, of Alzheimer's. Liz talked about this person who has short-term memory and is sometimes depressed, won't get out of bed, and has little appetite. And so it's good to know that there are drugs that can also help with that brain function. To get them motivated, so to speak. You did mention accelerated approval. You gave a timeline of about six months. Is that what we're really looking at?

Dr. Aisen: The landscape is pretty complex right now but there are, as I said, four drugs that will be reading out in phase three trials over the next six months. Phase three trials are the final stage in drug development, but there is a regulatory review process that follows. It's difficult to accurately predict exactly how much time it takes to complete that process, but there could be drugs available within months. That is early in 2023. It could take some months longer than that, but I'm optimistic that one or more of these drugs is going to reach clinical trials in the coming year.

Angela An: Can you maybe give an example of how the drugs are distinctive from each other and how they attack the disease?

Dr. Aisen: So each of these four drugs is, as I mentioned, an anti-amyloid drug, and in fact is an anti-amyloid antibody. But there are differences in what part of the amyloid they attack and the mechanism by which they reduce amyloid and how they are administered. So let me tell you a little bit more about them. The first one that we expect to hear about, which could be any day now is a drug called Lecanemab. None of these names are very user-friendly, so people may have trouble remembering them. They're not marketing names. These are the chemical names. So the first one is called Lecanemab. It's coming from a pharmaceutical company called Eisai.  Lecanemab was designed to attack a form of amyloid called a protofibril has to do with the size of the amyloid that is attacked and the antibody is administered intravenously. So as an infusion it is able to get into the brain a small amount of the antibody gets in and attacks a form of amyloid and enables cells in the brain to chew up the amyloid and clear it away. That's Lecanemab. The second drug that we expect to hear about within a month is called Gantenerumab. Again, not user-friendly names, but Gantenerumab is coming from a company called Roche. It attacks amyloid deposits. It's different from Lecanemab in that it is administered subcutaneously by injection, kind of the way insulin is administered, so it's a bit easier to take. It also clears amyloid from the brain. So in that, it's similar to Lecanemab, but a different mode of administration. And each of these drugs is gonna have somewhat different safety characteristics and we'll learn about their effectiveness as these trials are read out. The third one is called Donanemab and comes from Eli Lilly, and it's an antibody that is attacking a different part of the amyloid molecule. It's called the in-terminus part of the molecule. It is a very rapidly effective antibody. And this rapid, robust response we're very excited about, and that trial of Donanemab is administered intravenously. That will be coming out probably around March or April. The fourth drug is called Solanezemab. Another antibody, but this one attacks the smallest piece of amyloid called the amyloid monomer, and appears to be substantially safer than the other drugs. But rather than removing deposits from the brain, it's attacking smaller pieces of amyloid. And we're optimistic that that will slow the progression of the disease. So there are significant similarities but also important differences among each of these drugs that we'll be reading out.

Angela An: We're certainly not advocating one drug or another. We're telling people that these are the trials that are going on out there, that ATRI has helped advance. So as you talked about that, I can feel the needle moving Dr. Aisen, I really can. It's exciting.

Dr. Aisen: It's very exciting and we've never been in this position before with so many drugs at this final stage of testing. But at the same time, as I mentioned earlier, at the earliest stage, we think the disease is driven by amyloid, but as it progresses, there are other abnormalities and we have to keep working on other therapies. There are two abnormalities, plaques, and tangles, and all of these new drugs are attacking the plaques. We're also working on drugs that attack the tangles, and those are based on a different protein called Tau, and we've gotta keep moving forward with those therapies, trying combinations of therapies, treating other aspects of the disease. There's a vascular component to the disease, for example. We still have work to do to get this completely under control. But advances in the field are making all of these targets tractable, and manageable, and the biggest advance in the field is the development of blood tests, which are facilitating the development of drugs. In the past when I started working in this field, we really had no way of telling what was going on in the brain. We couldn't see it with scans because the changes are microscopic and we couldn't see it with examinations or blood tests. In a sense, we were shooting blind as we tried. To test drugs, we often enrolled people who didn't even have the abnormalities we were trying to treat. That has all changed just in the last few years, and that's part of the reason for all of this progress. We now have blood tests that are terrific. These blood tests can show us whether there's amyloid in the brain, blood tests that can show us whether there are tangles in the brain, blood tests that can help us select the right dose of a drug because drugs that remove these abnormalities also change these blood tests and we just have much, much better tools. And as these drugs come onto the market, we have these blood tests that will enable us to find the right people to get those drugs. So the development of very accurate blood tests for Alzheimer's disease has been just an enormous advance in the field in the last few years.

Angela An: That's so exciting for someone who maybe is entering this world of Alzheimer's and has a family diagnosis. I mean, you can imagine, as we all know and have been there, the influx of information and words and drugs that you can't even spell, right?

Dr. Aisen: We now have scans that can show the plaques and tangles and those scans developed over the last 15 to 20 years. They're called amyloid pet and Tau PET scans. They can show us these lesions, these abnormalities in the brain, and where they are and how they're changing. And they are still the gold standard, allowing us to visualize this disease. But the blood tests are highly accurate. And closely correlated with the PET scans. We're still in the final stages of validating these blood tests. We're already using them in all of our clinical trials, but I wouldn't say that they take the place of scans because you can't see the deposits, you can't see the spread of the abnormalities. You see the geography of the brain abnormalities with blood tests, but the tests, the blood tests are so accurate that yes, I think in coming months and years, we will be increasingly replacing scans with blood tests.

Angela An: I love it. Dr. Aisen some people may not know, but you are the founding director of ATRI, the Alzheimer's Therapeutic Research Institute there in San Diego at the Keck School of Medicine. You talked about diversity inclusion and how critical that is, especially given some controversies surrounding some treatment. So what do you do on a broader level to make sure that all parties are represented, and that these drugs are really going to be effective for people who do have a variety of histories and backgrounds?

Dr. Aisen: So let me just start by saying that not only in our field, in Alzheimer's disease, but in all fields of medicine, we depend upon people volunteering for studies so that we can test drugs before they come to market. And we conduct these studies. The studies are conducted in a very rigorous scientific way so that the results are reliable, but they're only reliable for the population that participates in the testing. And we, in our field, as in every field of medicine, have failed to have truly representative populations in our trials. The trials tend to be homogeneous. It tends to be highly educated people and people in urban environments that understand clinical trials and volunteer to participate in trials and the populations just have not been representative of the US population that we wanna help with these treatments. And so that's a failure and we have to address that. And it is not easy to address that because it requires that we build trust. In all communities, people feel that they want to be part of the scientific investigation and they are interested in volunteering to participate in clinical trials. That requires trust. There's a history of mistrust for good reasons. People have not been treated with care and oversight which is essential to ethical research and drug development. And there has been mistrust that has contributed to the lack of representative populations in our trials. And so to address this we have to engage with communities, all communities, and rebuild trust and exchange information and create partnerships that will allow us to work with the entire population of the US in our trials so that when we see that a drug is effective, we know that's it's effective for everybody. Not just people in San Diego or in Chicago or in Columbus, but everybody from every community, all races, all ethnic groups around the United States. We wanna know that these drugs are safe and effective for everyone. It's a big effort and it takes time, but we are devoting a huge effort now to building trust, to engaging with communities, and increasing diversity in our clinical trial populations. One of the ways we're doing this is by going out into the communities and doing screening in the communities. Coming back to our talking about blood tests. The blood tests are helping us do this. Rather than bringing someone into an academic medical center, we can go out to someone, even in a small rural community, for a blood test that gives us huge information about risks and abnormalities in the brain, essentially allowing us to bring the science to them, right? And that reduces barriers and will help us gain more representation in populations in our trials.

Angela An: That is so meaningful, Dr. Aisen because it's all about accessibility, right? And I think as we have seen in the last two years, so many gaps when it comes to other things, especially Covid, exposed that to us. And so the fact that you are saying, "we're gonna make this accessible, we're going into the rural areas," and just like food deserts, there's probably research deserts in the country, right? There are small parts of middle America people don't even know exist.

Dr. Aisen: Yeah, we have centers all across the United States, but not everywhere. And they tend to be located in big urban areas and we have to make big efforts to connect with everybody.

Angela An: We have a couple of more questions and I'm gonna finish with one from myself that might get a little personal with you, Dr. Aisen, and I hope you don't mind. I feel like we're friends now, but my grandfather had Alzheimer's before he passed. And you know, deep down in, in the back of my mind is this fear, right, of, will my father get it? Will I get it, Will my child? What will happen? And so I play Sudoku every day. I have brain games on my phone every day that says if you can do this and you're 3%, then you, you know, you have a memory of a 20-year-old or something. Are there really effective things people can do to prevent Alzheimer's?

Dr. Aisen: Well, it's a great question and we all want the answer to that question. I will say that we still have a lot to learn, but the way I see it, there are two aspects to this disease that we should think about in terms of prevention. One is the biology of the disease, which has to do with, again, the amyloid plaques and the tangles, and I think the way to prevent that abnormal biology is probably going to be with specific medications that treat the abnormalities that lead to those lesions in the Alzheimer's brain. But that's only half of the story in a sense. And the other half is what we would call the resilience of the brain. How well does the brain protect itself from abnormalities? To what extent can the brain develop new connections and robust connections that withstand those abnormalities? That's resilience. And we now understand that there are ways of increasing brain resilience that can help delay or reduce the onset of Alzheimer's, and we think a number of lifestyle changes can help improve brain resilience. We think that brain activity, educational activity that continues throughout life, can be helpful. We think that social activity, and engaging with family and with communities can be helpful. We think that a healthy diet can be helpful, a Mediterranean type diet, the type of diet which is good for cardiovascular disease, we think helps with brain resilience against Alzheimer's disease. Physical exercise helps factors that protect brain cells. And so physical exercise is helpful. I think attending to medical conditions that we think can aggravate Alzheimer's, like not only vascular disease but diabetes, tending to blood pressure abnormalities, all of these things we think can help with brain resilience. So what I would say to everybody is that a healthy lifestyle, with physical exercise, social interactions, brain stimulation, a healthy diet, and attending to blood pressure and blood sugar, all of these things can help improve brain resilience.

Angela An: And honestly, everything you listed is probably what everyone's primary care physician tells them to do as well, right? You talk about being healthy inside out. You spelled it out right there. I know we only have a few minutes left and we have such attentive viewers or Zoomers or people who are watching. I wanna end it with this question for you, Dr. Aisen you know for me my family connection. But working at ADRC for three or four years and seeing so many families come through, I would say the silent suffering of caregivers, watching their loved ones have their memories stolen from them, was heartbreaking. So for me, doing things like this and getting the word out there about your research is what motivates me. What personally motivates you when you wake up and say, I'm gonna conquer this today?

Dr. Aisen: I think in a sense I'm motivated the same way everybody is eager to see improvements in public health and in our ability to prevent and treat this disease. Yeah, it's affected my family, just the way it's affected most families. I see this as one of the greatest unmet needs, effective treatment for Alzheimer's disease. There's nothing that's more feared as people get older than developing Alzheimer's disease, developing dementia. I think we can make a huge difference in this, and I think that it's incumbent upon all of us to work as hard as we possibly can toward bringing effective therapies as quickly as we can. And for scientists, that means just working, collaborating, sharing, and working together. And I think that we're doing that and for everybody, it's volunteering for studies, participating in research, and taking care of ourselves with lifestyle changes. I think we have to do all of these things and it's exciting that we're on the cusp book major breakthroughs, but we, we still have to gather together, work together, and we'll make huge progress.

Angela An: I love it. And you talked about people also needing to get involved, so we'll end it with this because people are asking how do they learn about these studies that you talked about that are enrolling patients in the San Diego County-area? Because there are so many, of course, they can go to the ATRI website and there's probably a litany of info, but is there a clearing house for this kind of stuff so they can pick and choose what's best?

Dr. Aisen: I will just mention some resources that people can use. The Alzheimer's Association has a great website and resources on clinical trials. There's clinicaltrials.gov, a government website on all clinical trials, but we have lots of programs here. We also have a web-based program where people can actually sign up on their computers or their smartphones and participate in research without coming into centers. Our web-based study is called aptwebstudy.org, and that's another mechanism people can use to learn about the disease and connect with investigators.

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