Aaron Carroll talks with Dr. Bruce Lamb and Dr. Alan Palkowitz about Alzheimer's disease. They discuss how they're combining their different backgrounds and strengths – basic science in university research for Lamb and drug discovery in the pharmaceutical industry for Palkowitz – as they work to develop potential treatments for Alzheimer's disease.
This episode of the Healthcare Triage podcast is sponsored by Indiana University School of Medicine whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence in education, research and patient care.
IU School of Medicine is leading Indiana University's first grand challenge, the Precision Health Initiative, with bold goals to cure multiple myeloma, triple negative breast cancer and childhood sarcoma and prevent type 2 diabetes and Alzheimer's disease.
Dr, Aaron Carroll: Welcome back to the Healthcare Triage Podcast. Today, we're going to be talking about Alzheimer's disease. This Healthcare Triage Podcast is sponsored by Indiana University School of Medicine, whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence in education, research and patient care. IU School of Medicine is leading Indiana University's first grand challenge, the Precision Health Initiative with bold goals to cure multiple myeloma, triple negative breast cancer and childhood sarcoma and prevent type 2 diabetes and Alzheimer's disease, which of course is our topic for today. We have two guests today. The first is Alan Palkowitz. He is the senior research professor of medicine and president and CEO of the Indiana Biosciences Research Institute. Also joining us is Bruce Lamb. He is director of Stark Neuroscience Institute. Welcome both of you.
Dr. Alan Palkowitz: Thank you.
Dr. Bruce Lamb: Thank you.
Dr. Aaron Carroll: So we usually like to start off by asking people how they got to the position that they're in. How does one become a senior research professor of medicine, Alan, and what is president and CEO of the Indiana Biosciences Research Institute? So if you could tell us a bit about what you do and how you got here.
Dr. Alan Palkowitz: Yeah. So thank you very much, Aaron. So I think my experience has been somewhat atypical in terms of coming into academia. I spent 28 years at Eli Lilly and Company started off as a bench level scientist, a medicinal chemist, and eventually in my last 11 years was a vice-president of discovery, chemistry research and technologies where I oversaw small molecule drug discovery across all the areas of therapeutic interest at Eli Lilly. So this was a very rich experience. And after being there for quite some time, I had the opportunity to take an early retirement at the end of 2017. And I was thinking about my next steps. And I had developed a long relationship with Anantha Shekhar who as everybody knows he's the key leader here at IU School of Medicine and he asked me to come over and help with the Precision Health Initiative and any perspective that I could provide and input and things kind of transpired.
And I came over as a professor of medicine and eventually met Bruce and hear a lot about our work together here in the past year and really created some great synergies. And then as I spent some time at IU, another opportunity came up in the community and this was the Indiana Biosciences Research Institute, which is an organization that really had kind of blossomed out of a vision to really create additional note of innovative research and capabilities that would draw the community together. And the IBRI had been around for about five or six years, and now I'm there to really help create additional bridges and create new scientific directions that really elevate the sciences here in the Midwest and hopefully beyond.
Dr. Aaron Carroll: Right. And Bruce sort of, what has been your experience? How did you get to here?
Dr. Bruce Lamb: Thanks a lot Aaron. So I'm a PhD level, basic scientist by training. I was at Johns Hopkins at Case Western Reserve University and in Cleveland clinic and doing basic science research into Alzheimer's disease actually for my entire career. And then I saw this opportunity to come to Indiana in early 2016 to lead this translational neuroscience research Institute called the Stark Neurosciences Research Institute. And it's a really unique place that brings together clinicians, basic scientists, translational people, now, drug discovery as well, brings everybody together into one location to really do innovative and interdisciplinary research.
Dr. Aaron Carroll: We wanted to talk today about Alzheimer's disease. So I'd really like to start by just for our listeners, what is Alzheimer's disease?
Dr. Bruce Lamb: Yeah, so Alzheimer's disease is obviously a brain disease and it was first described. And I think the history is important because it's still how we've viewed the disease was described by a Bavarian neuropathologist, Aloysius Alzheimer in the early 1900s. And he had a patient who had dementia, loss of memory. She had paranoia. So there was a whole set of clinical features that she had. And then when she died being a neuro pathologist, he looked in her brain, did standard stains at the time and described this unique brain pathology, which still even today defines the disease. And there was primarily that there were two primary major neuropathological hallmarks that he observed in the brain tissue, one where these amyloid, this sticky substances which were aggregating in the brain. And the other was what we taught currently today called neurofibrillary tangles, which is another brain pathology.
And even today, it's still those two primary brain pathologies that are pathognomonic for Alzheimer's disease. However, I will say that as we've gotten into the modern age and I began to understand the complexities. We appreciate that Alzheimer's disease is a complex set of probably multiple disorders, which are very related to one another, but actually there's probably not one set of Alzheimer's disease out there.
Dr. Aaron Carroll: So is it just like a neurodegenerative cognitive decline that is, we just believe is because of a few specific reasons? So there's clearly a lot of neurodegenerative cognitive decline syndromes, but Alzheimer's is just a group where we think we know where the pathology is?
Dr. Bruce Lamb: Right. It defines one particular type. And again, there's many different types that this is probably the most common one and it's also very much age related. So you really see a doubling after about the age 70, 75 doubling every five years of the incidents. So with the baby boomers reaching the age of 65 at 10,000 a day right now, that's why there's the big increase in number of cases.
Dr. Aaron Carroll: Is there a typical course? Does it usually hit at a certain age and last a certain amount of time?
Dr. Bruce Lamb: It's pretty variable. There is a prototypical Alzheimer's disease, but if you talk to the clinicians and I'm not a clinician, but if you talk to the clinician and say, "If you've seen one case of Alzheimer's disease, you've seen one case of Alzheimer's disease." That really there's so much variation in how people present, how it progresses within those people. So it's pretty variable. I mean, obviously the one common underlying feature is certainly memory loss, at least at a general level. But within that you have other changes sometimes with personality disorders of all variety of other things that can come along with Alzheimer's disease.
Dr. Aaron Carroll: Given that it's a diagnosis based on pathology, how do you diagnose it when someone is still alive?
Dr. Alan Palkowitz: This is actually something that is an evolving science. I think for the longest time all we had were cognitive assessment tool, the series of questions that patients were assessed over. And I think probably within the past, maybe 15, 20 years, we've had some additional tools that have helped us more and more. We have imaging capability. So we actually can see and into the brain and see the presence of these pathologies that really help us to connect a cognitive assessment with what's maybe happening in the brain. But it's really a big challenge. And one of the things that the field is really pushing for is additional biomarkers or ways to be able to additionally assess through samples or analysis of samples that come from blood, or even other types of fluids that are associated with brain function that actually could give more insights into what's happening more fundamentally at the molecular level, if you will, that is driving some of these potential changes that are associated with the disease progression.
But it's highly imperfect at this time. And it's one of the areas that the field is really working to advance, which I think will be important for better diagnosing patients, understanding their disease and the heterogeneity of disease. So that we think about therapies in the future, we can really fine tune how we think about treating patients and changing the course of the disease.
Dr. Aaron Carroll: What are the thoughts on therapies at the moment? I mean, are there any therapies at the moment?
Dr. Alan Palkowitz: So really what we have are just a couple of therapies that really affect the symptoms called an esterase inhibitors really help with some of the symptoms that there is some positive effect. I mean, very marginal on cognitive function of patients, but nothing that really gets at disease modifying or really changing the course of disease in more fundamental level. There've been many, many drugs taken into a clinical study that have really built on some of where the field has drawn some of the primary learning around A-beta, for example, they made a hypothesis that the presence of these plaques, in advanced disease would be a viable target. And certainly many drugs have been assessed for this. Unfortunately don't have any positive outcomes. And the other pathology that Bruce mentioned Tau, the Tau Tangles, there's currently therapies being studied against those manifestations in advanced disease. But we haven't had any positive results that really would be of impact we would hope to demonstrate that affect the progression and even reversal of some of the damage it's done. We're just not there yet.
Dr. Bruce Lamb: Although there's this is sort of an interesting time because there is one anti-amyloid therapy called aducanumab, which targets beta-amyloid. They ran two trials, one that basically failed. And one that had some modest, positive findings. And based on that, and I think another internal data that they had, they actually have moved forward and went to the FDA to try to get approval of this drug. And it's going to be seen by the FDA on November 6th. So just around the corner, there's lots of different ideas I think out in the field of whether it will get approved or not. I think a lot probably depends on what's within that package that they've sent to the FDA and obviously nobody knows that except for the people within Biogen and the FDA.
Dr. Aaron Carroll: But if they're moving forward with looking for approval, I would assume they think they have results, which are positive.
Dr. Bruce Lamb: Yes. Although I think I, again, right now, since there is not much out there, there's a real desperation for anything as people say, there's a baseball analogy. This may be a single, or maybe even a walk but it's not going to be a home run. I think it's pretty clear.
Dr. Aaron Carroll: Why is it so difficult to find therapies for this?
Dr. Alan Palkowitz: Well Bruce mentioned that the disease was first characterized about 100 years ago. We've had a lot of advances in understanding some of the biology of the disease, the emergence of modern tools. I think we're still realizing the massive complexity of Alzheimer's disease and deconstructing the disease process. One of the things that we're beginning to appreciate more as Bruce mentioned, was the heterogeneity of the disease in terms of all the different factors that may be driving this end stage pathology. And I think a lot of the therapies have really focused on where the end stage of the disease and maybe not some of the primary early drivers that actually may set things in motion that actually are not addressable if you wait too long or actually go after the consequences of the disease and the damage it causes.
So I think these are the things that we're learning. I think we're also struggling with how we move earlier and earlier disease and understand what's happening before a patient may even be presenting with the symptoms we observe in some of the cognitive changes. And so I think this is where new initiative, new insights of disease that builds on all these findings from more recent efforts that are teaching us. Not only do we have to go earlier, but we have to understand more of the fundamentals of what drives the disease in individual patients, because every presentation is somewhat different.
Dr. Bruce Lamb: I would add just to that, that I think what Alan was talking about previously about beginning to get these biomarkers, I think is critical for that, because again, to help define patient populations is really, really important. It's just one example, some of the early anti-amyloid therapy trials, just brought patients in basically by clinical measurements of memory loss and things like that. And it turns out after the fact, they went back and found that I think about 30% of those cases actually didn't have amyloid at all. They had something else. So obviously that gets at the complexity of how, okay, if you're designing trials and you want to target a specific target and you don't have a way to assess whether the target is there, is really problematic. And again, and I think that's like all the new trials now are usually enrolling based on the brain imaging or some of the cerebral spinal fluid biomarkers.
But I would say that's still probably not enough. We're probably going to need additional biomarkers. There's a lot of work going on in the blood right now, which is actually really promising actually some of the data that was presented this summer suggests that this likely over the next couple of years, we will have some decent blood biomarkers too.
Dr. Aaron Carroll: So you mean that there'll be a blood test that would tell you if you have, if you're likely developing very early stages of Alzheimer's?
Dr. Bruce Lamb: Right. But you would be at risk, basically, I think it would be viewed more as like getting your cholesterol measure, that there'd be a biomarker that would help you identify for somebody who might go on to develop the disease.
Dr. Aaron Carroll: It's interesting because it's like, it's one of those in my head I'm like, is that it feels like a chicken and an egg kind of thing. It's like, it would be great to pick up people who are early, but then of course we need something to do for them if we pick them up early. So are we trying to develop both of those things at the same time or is there an order to it?
Dr. Bruce Lamb: It's pretty much simultaneous. I think we're trying to, and actually, and maybe Alan can talk about that. That's one of the things we're thinking about with, for example, the drug discovery center that we need sort of, yes, we need the therapies moving along on one avenue. But we need this other pathway where we're identifying biomarkers we're going to be able to use to push those therapies into the clinic. And Alan, I'm sure you can comment more on that.
Dr. Alan Palkowitz: Yeah. And that's what's so exciting, is it? I think as we move forward, I think the discovery new therapeutics are going to go hand in hand with the discovery and assessment of potential biomarkers that may be tied to very specific mechanisms that we're exploring. And I think as we move forward, the preclinical stages of taking a new idea in terms of the intervention approach, and we're looking at a cellular and in vivo models, these things need to talk to one another very closely because what we really have to make sure is, and where I think there's been a contribution to the failure in the past is making that leap between the preclinical and the clinical stages. We can do quite an impressive studies in mice. We can model different aspects of disease and show positive changes, but being able to leap into humans and actually have that prediction ability, I think is really an important challenge. So these tools need to work together. So as we're creating new molecules, the additional tools to actually allow us to study and monitor the disease, especially as we go earlier are going to be a critical components. And that's some of the great work that Bruce and his team are doing here at IU that I think couple very nicely with our drug discovery initiative.
Dr. Aaron Carroll: How does one study this in animals? I mean, how do you create a mouse? Do you have a mouse model for Alzheimer's? How do you do that? What does it look like?
Dr. Bruce Lamb: This is the space I've worked in for my entire career. And early on, most of the animal models were generated based upon a really unique set of Alzheimer's disease, which is a very early onset Alzheimer's disease, which is autosomal dominant. It's a genetic form of the disease that actually Aloysius Alzheimer's original patient actually was one of those, as it turns out. There we know that there's specific mutations that cause the disease. And I think that's really where the interest in amyloid came was really because a lot of the genetics of those families suggested that amyloid was potentially a driver because of the genes that were mutated in those families. And so that information was used to then generate animal models, where we introduced those same genes and mutations into animals to drive those disease processes. And we generate a lot of models that can produce lots of amyloid deposits in the brain.
And so we have those, but again, as we move forward into the clinical trials so far, we've not been very good at predicting what, based on animal models, what's going to work in humans. So I think there's a been a reassessment I would say over the past five, five to 10 years of where we are and how do we need to do better? And so out of that actually came in efforts to generate better and more predictive animal models and NIH actually put out an RFA or request for applications to do just that, which we applied for when I first arrived and we successfully competed for that, which is called MODEL-AD, which is to develop models for late onset Alzheimer's disease to try to get more models, the more typical Alzheimer's disease. That's also much more complex, the genetics is more complex.
There's clearly environmental factors that play a role, but we have a big team working on this across five different institutions and regenerating large numbers of animals. One of the huge advances and changes for animal modeling has been the advent of CRISPR and obviously, which was given the Nobel Prize this year and well-deserved, and that has just transformed our ability to first generate models. Because we can do it's far more easily and more cheaply. And really the major efforts we have are in phenotyping all the animals. So we have really a robust pipeline and we have some I think early results in some of our animal models that they really may be helpful for us. And then the last piece I'd say, we're really trying, especially with this, to align our information with the human disease, much more closely. So we're spending a lot of time, for example, trying to do all the various level of phenotyping and align that to the human disease. So that then at least we can feel like we can tell what are these models good for, and maybe what they aren't good for.
Dr. Aaron Carroll: Could you talk a bit about how your two groups work together? Because I think people might find that interesting how a neuroscience center and a drug discovery center, what do each of you do apart and then what do you do?
Dr. Alan Palkowitz: So when I first came over IU, within the first few weeks I met Bruce and we learned about a new grant opportunity that was being put forward by the National Institutes of Health to actually create a Alzheimer's disease drug discovery center with the specific goal of actually diversifying approaches to a new therapeutics discovery that were not based solely on advanced pathology and focusing on Tau and A-beta, where many previous efforts, including the bulk of the industry effort has largely been focused. And it really was intended to build on a lot of the novel findings that are being contributed by researchers around the world, in terms of new ideologies, new potential drivers of the disease that are based on very complex human genetics and genomic studies from post-mortem tissues and other types of inputs that are shaping our early understanding and probably a more advanced understanding of the disease.
When I came and I met Bruce, Bruce had a very strong interest in this being associated with many, many NIH programs, the MODEL-AD program. And it was actually a perfect combination to now think about pairing a drug discovery capability with integrating aspects of the MODEL-AD program. Because that helps to complete the translational cycle, even if it's still in the early parts of drug discovery, but it positions output to really be on a path towards potential exploration in humans. And so we combined forces and we put together an application. I'd had never done that before. So Bruce was a tremendous help. And if I knew how much work it was before I started, I may have thought twice, but I've actually put together a very compelling proposal that brought some of the great resources together here at the IU school of medicine and with our partners at Purdue and some other subcontractors.
And we put together basically a very strong integrated program that allows us to take new target hypotheses, new ideas, and begin the process of drug discovery, and then pair them with an understanding of their potential in disease models. And then have that output as being potential molecules that could be further optimizing and carry forward into clinical study. So that's what we managed to create. It's been a, I think a bit of a whirlwind, but it's been really fascinating for me coming from industry where I did this in a very structured environment for that purpose to work with Bruce and all the talented scientists here to kind of create a new model for doing this work in an academic setting. Which has its own unique challenges, but certainly some other positive benefits that allows us to really freely explore ideas and really think out of the box of how we do our work.
So that's how we come together. But we work as a very strong team. We complement each other's strengths, and I think it's really important for aspects of therapeutic discovery that you have strong, scientific diversity in your team, different experiences, but also different fields of science that are represented. When you put it all together it becomes a very powerful force and we're very excited to be pursuing advances for patients in this regard.
Dr. Bruce Lamb: Yeah. I would say on the other side, it's been a great learning experience for me. One of the things I say is if any, I think it works both ways as Alan was describing for the drug discovery and academia obviously have different environments, a different way of working. And I'm the same, the other way I've been in academia my entire career. And so when it came to drug discovery, this is something I don't have experience in, I don't think about every day, but to bring those two together, especially with the right team members, team members who can really say, "Look we're all in this together and we need to work together to do this." Has been fantastic.
And I will say that the diversity of, especially for the drug discovery center of expertise of perspectives across the team is remarkable. And I've never worked in an environment like that. And so I actually, I find it really exciting and stimulating going to the meetings because every time I feel like I'm learning something new and getting exposed to something that I hadn't before. But obviously the key for all of that is having the right team members, the right people who can all participate in that manner. And that's not for everybody, for sure. There's definitely people who I think would not fit into that.
Dr. Aaron Carroll: What are you most excited about right now with respect to the work you're doing?
Dr. Alan Palkowitz: One thing that I'm particularly excited about is the promising data and supporting science suggesting our area of focus, which is neuroinflammation has we believe some very strong potential to really not only enhance our disease understanding, but hopefully provide us on a pathway to some really testable hypotheses and patients that may have very strong potential to help the disease. And a lot of that has been shaped by some of the expertise including Bruce and his team that we have not only here at IU, but what the broader scientific community is telling us. And I think that's where it's very, very exciting when you see this collective wave of contribution from across the globe, suggesting some potential new direction, and then how can we couple our capability to take advantage of that and take it to the next step?
And I think that's what's very, very exciting and I think that's what helps propel science forward and advancement. I mean, at some point we all have to take a leap of faith in our work and choose what to work on and where to focus with the hope that that's the best choices with the time and the resources we have. And so once you create a momentum behind that, it really is exciting journey to then find answers. And especially for such a difficult disease where there's such a strong need and a strong pool for answers and solutions. And so I can't imagine a better position to be in to be able to impact that chance.
Dr. Bruce Lamb: Yeah. And I would just add, I think the thing that I'm really excited about right now, especially in IU school of medicine and in the broader community here is the breadth of expertise and experience and programs related to Alzheimer's disease from very, very basic science and structural biology to all the clinical incredible clinical work that's going on. There's just so many different things and again, ind a great leadership across all of those areas. And so that makes me really feel like we have the potential to really make a big impact in terms of the disease.
Dr. Aaron Carroll: Are you most optimistic about treatments, do you think, or earlier diagnosis or prevention, all of the above, where do you think the big breakthrough is going to come?
Dr. Alan Palkowitz: I think ultimately, I mean the big breakthrough that everybody wants to see is a therapy, but the path with therapy I think will provide these additional tools that help us to better understand patients so that we line up patients with the best therapy options we find the best time to intervene, even though it may not seem so obvious. And I think the new tools of science that we have at our disposal to really understand individual patients at a fundamental genetic and proteomics level. Tell us more about how we can take that new molecular understanding of the disease and individual disease and return that as a solution, not only in terms of a therapy, but associated tools that really help us not only diagnose, but also track the progress of therapies. I think this will come as a collective and not just as individual components, at least in my view.
Dr. Bruce Lamb: I think within the larger group, as I was mentioning because we have people working all the way to then more going out into the communities and helping people. I think we have the potential for a number of different areas to have potential impact. Obviously I think that some of the major programs with the drug discovery center, the MODEL-AD center, there's also a longitudinal study of early onset Alzheimer's disease led by Liana Apostolova, which is a huge national study of early onset Alzheimer's disease. Each one of those, we have a potential to make an impact in some of the things you just mentioned obviously biomarkers we've already talked about that's certainly something we're working on. Obviously bringing therapeutics forward to the drug discovery center, learning more about the disease, like the study of leads of the early onset Alzheimer's disease. What does that look like? Which we still don't really have a good handle on. So I think there's a lot of areas that we, I hopefully will have an impact on.
Dr. Aaron Carroll: Well, this has been fascinating and clearly there's going to be news in the future. And as progress is made, we'd love to have you back and discuss exactly what you've seen and where we should be looking next.
Dr. Bruce Lamb: Great. Thank you so much.
Dr. Alan Palkowitz: We'd be happy to do that. Thanks so much for the opportunity
Dr. Aaron Carroll: Thank you. This Healthcare Triage Podcast was sponsored by Indiana University School of Medicine, whose mission is to advance health in the state of Indiana and beyond by promoting innovation and excellence in education research and patient care.