How Alzheimer's Drugs Work with David Gate, PhD

[00:00:00] Erin Spain, MS: Today, we are diving into new research on the fight against Alzheimer's disease with Dr. David Gate, Assistant Professor of Neurology in the Ken and Ruth Davee Department of Neurology and Director of the Abrams Research Center here at Feinberg. We had Dr. Gate on the podcast in 2022, soon after his arrival to Northwestern, to talk about his lab's research on immune contributions to neurodegenerative diseases. Specifically Lewy Body Dementias. But Alzheimer's disease has long been a focus of Dr. Gates work and a new paper recently published in Nature Medicine his team used advanced techniques to investigate what happens in the human brain after certain Alzheimer's therapies were administered and his team identified new molecular targets that could make these Alzheimer's therapies more effective and not only slow disease. But improve outcomes for patients. We are very excited to talk to him about this new research. Welcome to the show. Dr. Gate 

[00:01:01] David Gate, PhD: Thanks so much, Erin. It's a pleasure to be here. 

[00:01:03] Erin Spain, MS: Well, let's refresh our listeners memories. You were on this podcast, as I mentioned in 2022, that was soon after you established your lab here at Northwestern. Tell me about your work here and what's progressed since you established your lab in 2021. 

[00:01:18] David Gate, PhD: Yeah, certainly. It's hard to believe it's been three years since that work was finished. But we've been on to new and bigger things, and as you mentioned, we've been interested in studying Alzheimer's disease, and in particular Alzheimer's disease therapeutics. It's been in the news recently that there are new Alzheimer's drugs that are facing some controversy in how well they work to treat Alzheimer's disease and we're agnostic to that, whether these drugs work as well as they should or don't. We're interested in how they work and how we can improve their efficacy to improve patient outcomes. 

[00:01:57] Erin Spain, MS: And that leads to the study that we're going to talk about today. Before we get into that, I want to also talk about a new center that you are the director of, the Abrams Research Center on Neurogenomics. This is within the Feinberg Neuroscience Institute. Tell me about this exciting development. The center is fairly new, only a few months old. 

[00:02:18] David Gate, PhD: Yeah, we broke ground in October in brand new lab space at Feinberg School of Medicine. We're very fortunate to have received a donation from the Abrams family based here in Chicago. And the center's focus is on Alzheimer's disease and our intent is to leverage sophisticated new age technologies and artificial intelligence to try to get new information to try to identify new therapeutic targets for Alzheimer's disease. 

[00:02:45] Erin Spain, MS: So Alzheimer's disease is the most commonly diagnosed form of dementia in older adults. Where does Alzheimer's disease research stand at the moment? You mentioned there's these new therapies, there's been some controversy out there.what are some of the unknown questions that your lab is working to understand? 

[00:03:02] David Gate, PhD: The controversy is not so much whether or not these drugs work. I think the controversy is more so They don't quite work as well as people would like them to. is part of drug development. It takes decades to get successful drugs. The brain is historically extremely difficult to treat. So, the cause of Alzheimer's disease is thought to be due to the buildup of an abnormal protein in your brain. And this protein is called amyloid beta. And in the late 1990s and early 2000s, there was some exciting research that showed if you vaccinate mice, with amyloid beta, that you could prevent Alzheimer's like symptoms in those mice. And so this led to a clinical trial in humans where they vaccinated humans with amyloid beta. It was called AN1792. That trial for AN1792 ultimately failed, but it really told us a lot about how to treat Alzheimer's disease because in the process of vaccinating patients with amyloid, we had some side effects. And so the, course of action that pharmaceutical companies took was to circumvent the Vaccination process and to simply immunize patients with antibodies and these antibodies are Directed and specific for various forms of amyloid. And over the years there's been clinical trials on these anti amyloid antibodies and they work to varying degrees of success, but they are in my opinion They're getting better and we're learning a lot as each drug comes out. And so targeting amyloid beta right now is still the prevailing therapeutic strategy. the trial for AN1792 was canceled because some patients developed brain inflammation. But When we and my collaborators looked at these brains after the patients had died, we found that amyloid was removed from some of these patients brains, suggesting that it was actually effective at removing amyloid. And so we've, in this study, intended to understand how amyloid was removed from those patients brains. And for the patients whose, who did not have amyloid removed from their brains, why was that the case? And we found some very interesting differences between those two groups. 

[00:05:27] Erin Spain, MS: Why did you decide to go back and look at that failed clinical trial and obtain the tissue of the brains of those folks who participated in the trial? 

[00:05:36] David Gate, PhD: Yeah, well this actually goes back to my PhD days when this research was being done. I was a young scientist and I had been reading about these papers and I was fascinated by them. And when I got my own independent lab, I really wanted to study these brains because they had always just really intrigued me. And so I simply reached out to the researchers in the UK who had studied these brains previously, and I wanted to study them with a new technique called spatial transcriptomics. And they were extremely enthusiastic about collaborating with me because They knew that this method was the way that they could get the types of information that they had been seeking over the years. What are the actual molecules that drive removal of amyloid beta from the brain in response to these drugs? 

[00:06:25] Erin Spain, MS: So you mentioned these advanced techniques that you're able to do in this study. Now, a lot of this is a result of the new center here at Northwestern, which you're the director. Is that right? 

[00:06:36] David Gate, PhD: That's exactly right. The center has allowed us to do this research because of the amazing equipment that we've been able to purchase, the amazing infrastructure and lab space that we now have. It's been instrumental in our ability to complete this research. 

[00:06:51] Erin Spain, MS: So take me through the process. So you were able to reach out to the folks in the UK, just walk me through exactly what you were able to obtain and the steps that you took to complete this research. 

[00:07:01] David Gate, PhD: Yeah, we actually received. brain tissue sections on glass slides. So they flew over the Atlantic ocean to get to our research lab. And we started processing them right away. And we were actually the first lab to have a machine for spatial transcriptomics called a CytAssist machine. We actually have a serial number on the back of our machine that says number one. So this was the first machine in the world to be used. And we feel like we've used it in a very efficient and positive way to try to understand the patient's response to these drugs in the brain. And to do this we had to learn this technique. We had not ever done this before, but to do this, we essentially, analyzed RNA molecules inside of the tissue. And we did that with spatial resolution so we could identify where in the tissue the RNA molecules came from. So when we're looking at a brain, for instance, that has amyloid removal, we can look in areas where the amyloid was removed and look at the RNA changes. So we know from which cell that RNA change came from and what that change might be doing to amyloid, how it was removed. 

[00:08:17] Erin Spain, MS: So let's talk through some of these findings. This is really fascinating work. Like you said, the first time that scientists have been able to look at the tissue in this way, what did you find? 

[00:08:27] David Gate, PhD: Like I said earlier, we found that there are basically two groups of people. There are those that responded positively to the vaccine and amyloid was removed from their brain. And there's a group of people that did not have appreciable amyloid clearance or removal from their brains. So with spatial transcriptomics, we identified the differences between those two groups and we also compared them to people who had Alzheimer's disease that were not part of this clinical trial and did not receive the vaccine. So what we actually found was that there's a type of immune cell in the brain called microglial cells. We did not discover these cells. These have been known for decades. Microglial cells are critical to the brain. They are the brain's resident immune system. They actually enter your brain when you are an embryo in the womb. And so your immune system is part of your brain. And these cells are basically the first line of defense. If you have an infection or an injury, they will go to that site and try to clean it up. Now, in Alzheimer's disease, they have dual functions. They try to help. They try to clean up the amyloid from the brain to make the brain function better. But they, in this process, they appear to become inflamed. They participate in inflammation. And so the trick here, I think, is to find that balance, what, how to make microglia good and how to make bad microglia turn into good microglia. And I think we're getting closer to potentially doing that, to take sick microglia or to take microglia from a sick person's brain and modulate them therapeutically to make them function better. But to do that, we have to know how do they function. What are those functions that we want to alter to make them better? And that's what we've learned from this study, is the exact targets that we want to try to hit to make these drugs more effective. And in addition to these patients who received an amyloid vaccine, we also analyzed a patient who received a new age Alzheimer's drug called Lecanemab. And this is an antibody against amyloid beta. And we found very similar genes of microglia that mediated clearance of amyloid in that patient that were remarkably similar to those that we had identified in the vaccinated patients. So this told us that amyloid is removed in a very similar way between those who are vaccinated with amyloid beta and those who receive antibodies to amyloid beta. 

[00:11:06] Erin Spain, MS: Now you've published this paper in Nature Medicine. This information is out in the world and available for all other scientists to download and understand. What do you want to see happen next? 

[00:11:17] David Gate, PhD: We're really interested in pharmaceutical development. We want to treat patients. I think with this information, we can start getting into preclinical strategies and finding what. What might be the best ways to alter these microglial cells to make them more efficient at clearing amyloid from the brain? We think that we might be able to identify how side effects occur in response to these drugs. We have data from some patients who have incurred some of these side effects and so we're trying to identify ways in which the immune system might potentially participate in these side effects and could be altered to mitigate them. 

[00:11:59] Erin Spain, MS: Would some of that work happen here at Northwestern, the next step into possible? to bedside, translating this into a clinical trial. Could that happen here? 

[00:12:08] David Gate, PhD: Yeah, absolutely. This research will be happening at Feinberg. It will be happening in the Abrams Research Center on Neurogenomics. We have several studies that are offshoots of this work, and we're really excited to develop those and to further the research of the center. And we think that positioning the center in this way to study humans that have been given therapeutics for Alzheimer's disease is really a great utilization of our resources here. 

[00:12:37] Erin Spain, MS: What can we expect in the coming months and years from the Center and your lab? 

[00:12:42] David Gate, PhD: Well, in the next few months and years, I think our goal is to get this research out to the public to make sure that we are doing our due diligence that not just the public, but our fellow scientists and colleagues are aware of this research and that they can build upon it. One of the key elements of this paper is that we are making all these data publicly available so people can interrogate the data themselves and interact with it. Our colleagues can download the data and analyze it themselves. So I think public awareness is a key thing for me over the next few months to make sure people are aware of this work. In the following years. The work never stops and Alzheimer's disease, I, I hate to say, but we're far from a cure.We are interested in studying living patients, too, because after all, we want to try to treat patients that are living with the disease. And so we're enrolling patients in a study in which we're studying patients who have been given new Alzheimer's drugs and looking at their response to those drugs. Try to get closer to that beginning stage of the disease and try to treat people before they really have the types of memory problems that are classically associated with the disease. And we're just now getting artificial intelligence tools off the ground and applying that to our data sets, which is extremely exciting because our data sets are just getting larger by the day. And to be able to leverage artificial intelligence against those data, we can probably discover things that the human mind would not have been able to decipher? 

[00:14:19] Erin Spain, MS: Thank you so much, Dr. David Gate for coming on the show and explaining this fascinating research, really one of a kind stuff coming out of Northwestern University. Thank you. 

[00:14:29] David Gate, PhD: Thank you, Erin. It was my pleasure. 

[00:14:31] Erin Spain, MS: Thanks for listening. Please click the bell to receive notifications about our latest episodes and follow us on social media at NU Feinberg Med to stay up to date with our latest research findings. 

Physicians who listen to this podcast may claim continuing medical education credit after listening to an episode of this program.

Target Audience

Academic/Research, Multiple specialties

Learning Objectives

At the conclusion of this activity, participants will be able to:

1. Identify the research interests and initiatives of Feinberg faculty.
2. Discuss new updates in clinical and translational research.

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The Northwestern University Feinberg School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

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The Northwestern University Feinberg School of Medicine designates this Enduring Material for a maximum of 0.50 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

American Board of Surgery Continuous Certification Program

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Course director, Robert Rosa, MD, has nothing to disclose. Planning committee member, Erin Spain, has nothing to disclose. FSM’s CME Leadership, Review Committee, and Staff have no relevant financial relationships with ineligible companies to disclose.

All the relevant financial relationships for these individuals have been mitigated.

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