The State of Alzheimer’s Research, with Dr Marcia Ratner & Dr James Hendrix | EDB 255

Dr. Marcia Ratner & Dr. James Hendrix discuss recent developments in Alzheimer’s research.

(VIDEO – 29 mins) Dr. Marcia Ratner, world-leading neurotoxicologist and research scientist at the Boston University School of Medicine. Her research focus is neurotoxicants, chemicals that can cause brain damage. Marcia is also a project manager for the Department of Pharmacology & Experimental Therapeutics at Boston University, and she also provides neurotoxicology-related consulting services resulting in major court decisions and policy change involving neurotoxicants. Dr. Ratner is also the Director of Research for Different Brains. For more information about Dr. Ratner, visit: www.neurotoxicants.com

Dr. James Hendrix is the Chief Scientific Officer at LuMind IDSC. In that role, Dr. Hendrix directs scientific initiatives for LuMind IDSC. A critical element of his role is to establish the nationwide Down Syndrome – Clinical Trial Network (DS-CTN) and to oversee the first clinical trial in the DS-CTN, the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study. The LIFE-DSR study is a natural history study focused on adults 25 years of age and older at high risk for Alzheimer’s disease. Dr. Hendrix is also focused on building potential collaborations with industry, academic and government scientists focused on Down syndrome research to maximize LuMind IDSC’s scientific impact. Prior to joining LuMind, Dr. Hendrix was Director of Global Science Initiatives, at the Alzheimer’s Association. For more about Dr. Hendrix and LuMind: lumindidsc.org

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DR HACKIE REITMAN (HR):  

Hi, I’m Dr. Hackie Reitman. Welcome to another episode of Exploring Different Brains. And today I was so lucky to have two of my friends coming back two of the world’s eminent researchers in Alzheimer’s disease, also Down syndrome. But we got two for the price of one today. We have Dr. Marcia Ratner of Boston University, of neurotoxicants.com and James Hendrix, the Chief Scientific Officer of Lumind, and because they’re smarter than me, I’m going to have them each introduce themselves more thoroughly. Dr. Marcia Ratner your first

DR MARCIA RATNER (MR):  

Hi, Hackie. I’m Dr. Marcia Ratner from the Department of Pharmacology and experimental therapeutics at the Boston University School of Medicine. And I also run a consulting business called neurotoxicants.com.

HR:  

Jimmy you’re up.

DR JAMES HENDRIX (JH):  

Hi Hackie, I’m Jim Hendrix, I’m the chief science officer from Lumind idsc. We’re a small nonprofit focused on dance and research. And, of course, we’ll talk about this more later. But we have a big interest in Alzheimer’s disease in Down syndrome.

HR:  

Okay, so without further ado, let’s get right into it. I want this to be the State of the Union in Alzheimer’s research. Now, I just mentioned parent theoretically, that of course, Down syndrome. Unfortunately, now if I have Down syndrome, and I live long enough, I have about a 90% chance of developing Alzheimer’s disease. But let’s start out with the State of the Union today as we speak 2021 in Alzheimer’s research, James will have you go first?

JH:  

Well, I’d say that the biggest news in the Alzheimer’s field in 2021, was the accelerated approval of a new drug by the FDA. In June of this year, this was the first drug of approved by the FDA, in I think 17 years for a brand new drunk, totally new drug for Alzheimer’s disease. This was a very controversial decision. We’ll talk more about the controversy around it. But this is also I’d say, a lot of people are opposed to the decision some people are we’re for it. But it’s definitely changed the landscape. And, and we can talk about how that’s how that’s making. Maybe the future look different than it was even just a few months ago.

HR:  

Marcia, you’re up at bat.

MR:  

So, you know, Hackie, I was actually interviewed about it, before it was approved. And at the time, I said that Biogen has a lot more work to do. And they’re doing that work. Now, you know, they’re doing a QA. This is an ongoing trial, even though it’s approved. There’s an ongoing trial, if there are any problems that surfaced, the drug will be pulled from the market. There were safety concerns along the way, the cognitive endpoints were not all met. And this is one of the first drugs it’s been approved for its clearance of a pathology implicated disease without really showing consistent clinical improvement. And this is very controversial, which is why there’s a what we sometimes think of as a phase 3B or a an an after approval or post approval kind of study so that the drug is not fully approved. And of course, it’s got a lot of hurdles to overcome. And so I said that we’ve cut the ribbon, but we haven’t broken ground yet.

HR:  

Okay, so what I want to do is put the drug to the side. Why? Because as exciting as it is, I’m looking at it either one of two ways, either it’s going to be the greatest thing since Pepsi Cola, which opens up the whole gateway to all these new drugs, and hopefully they’ll show a correlation between cleaning up all that de brie and the clinical implications. So that’s one scenario. The other scenario is it doesn’t pan out. Alright, which we hope it does, but jury’s still out a little bit though. It’s been approved. Now Let’s look at others. What’s the other stuff besides the one possible wonder drug?

MR:  

Right. So can I chime in? So, you know, be one of the targets of aducanumab are the obvious oligomers, which are smaller molecules and the big aggregates that we think of as plaques. And there are other drugs in the pipeline that are targeting these oligomers. And they’re in phase three trials now. And so the target is not, you know, all gone, the, I think, like I said, we’ve got the ribbon, we’ve got a lot to learn, we’ve got a lot to learn. And there’s a lot of information coming from this. But the oligomers, these oligomers, which are smaller than amyloid plaques are really starting to look like the target, that’s going to be the game changer.

HR:  

Okay. Now, Jim, at Lumind, you are trying to build lots of bridges and lots of partnerships, can you talk about some of the potential with them as it pertains to Alzheimer’s?

JH:  

As you mentioned, the Down Syndrome population is really affected by Alzheimer’s disease at an extremely high rate much higher than the general population. But even even with that, very few people would have been in an Alzheimer’s disease clinical trial. So that’s something that new mind would really like to see changed. Because, you know, as you advocate, as you know, for example, received accelerated approval from the FDA, but it’s never been tested in advance in the population. So we don’t know if this drug is safe or effective. There are papers out there that say it’s not appropriate for use in the downstream population. So that’s, that’s kind of, that’s pretty heartbreaking. You know, we finally have this approved dragon. And experts are saying it shouldn’t be used in the decimal population, because we don’t have enough data. So it’s something that we want to change. And, you know, we see other drugs coming down the pipeline, we see, there’s a there’s a rich Alzheimer’s pipeline of drugs. And we would just like to see more and more done. So a new line, we have a response during the study, called Life DSR, which is a natural history study, which means we observe adults with Down syndrome, and we we study them and we see how they might be progressing toward Alzheimer’s disease, we do test their cognition, we over time we test the function over time, we also take blood samples and look for biomarkers in their blood that could indicate the progression toward Alzheimer’s disease. So one of the things we’ve done recently, as we’ve been able to sign up a couple of big pharma companies to further support our research. And we’re expanding the work we’re doing to add a study on a type of assessment scale called goal attainment scaling, which is a way of caregivers can report how their loved ones are doing in a very systematic way. And we’re also expanding the biomarkers we’re looking at. So we’re going to expand to do how PET imaging. So this is a way of imaging the brain to get a picture of the living brain to see evidence of the tau prototype, the tau tangles that appear as someone presses toward Alzheimer’s disease. And we’re also going to be collecting cerebral spinal fluid. Again, it’s a sub study. It’s not the entire 270 that’s in our national history study. But we’re excited about getting this forward moving this forward. And we’re also excited to see companies showing interest in this very important population. It’s been frankly neglected for too long.

HR:  

Very good point. Marcia, how does this interface with the research you’re doing at Boston University?

MR:  

So you know, Hackie, I just had a paper come out where we’re looking at a compound called alpha five IA, which is a negative allosteric that means to modulate to site next to but not directly at where the neurotransmitter to involve inhibitory neurotransmission binds to the cell on this receptor. And we found that in Alzheimer’s disease, the response of the circuit to this modulator of this type of receptor called the alpha five type GABA-A receptor is lost in an animal model of Alzheimer’s disease. Now why this is important is one of the few drugs It’s been investigated for Down syndrome is fast missing now. And this compound failed to meet its endpoints, but its targets, it goes after the same target. And so we’re we certainly know that we’re, there’s a commonality here, there’s something that you can read the tea leaves and say, Well, what’s going on in downs? And what’s going on in marches for to get Alzheimer’s? And, and what might this tell us about different targets? But we’re optimistic that our work in Alzheimer’s will shed light on the down population, and help us to develop novel therapeutics.

JH:  

Let me let me just comment, one of my, one of the things I think is really important is that research is never done in a vacuum. And that we learn about one population can can teach us about another population. And, you know, there’s another population that Marcia didn’t mention, there’s this autosomal dominant, a population where people have a genetic mutation. And they then they get Alzheimer’s disease at a much younger age, that really onset age. So all of these populations, whether it’s Down syndrome, the sporadic at population, late onset population, and the ADHD population, could, they’re all can be studied in isolation, but what we learn about each of those populations can help inform our better and give us a better understanding of Alzheimer’s disease as a whole. And so I think that’s one of the reasons we need to do this research.

MR:  

So true, so true.

HR:  

And you’re both established, we’ve established the Alzheimer’s Down syndrome. Link, if you will, other any third players, any other players? Or is it just those two?

MR:  

Well, Hackie, there’s a company called Alzheon, and they’re working on it, orally bioavailable compound that targets the oligomers. And this is one of the compounds, it’s in phase three clinical trials. If that’s successful, it will be a big benefit over at kin map, which requires infusions. And it’s, the delivery is very difficult and invasive. And obviously, for the Down Syndrome population raises a whole other level of complexity. If that compound is successful, it may be a easier clinical trial to get approved and tested in the Down Syndrome population where you’re not going to have to do these infusions.

HR:  

Jim, you have something to add to that?

JH:  

Well, I would just comment that we have in the shorter term, we know that the Agile home approval has opened the door and kind of created a precedent for with the FDA for how to get new drugs approved. So Eli Lilly has announced that they’re going to go with their MP amyloid antibody to the agency next year using the same approach that Biogen did to get as your home approved. And then there’s, there’s two others that are in the same class. And so I guess I would be really, really depressed. If as your home were approved, and there was nothing else coming in the pipeline. So we’d be stuck with this very controversial, somewhat flawed, or potentially flawed drug. And we’d have nothing else to compete with it for the foreseeable future. But that’s not the situation we find ourselves in. And I think that that’s what’s exciting, encouraging is that we’re right, there’s there’s other candidates that are working with through the pipeline. And there’s other approaches, as Marshall mentioned, and I think, you know, there’s some anti tell therapeutics that are in the pipeline as well. And the thing that I really want to say, the thing that that I am most excited about, is that someday we’ll be able to do combination therapy and Alzheimer’s disease because we know complex diseases like cancer, and other diseases are most effectively treated when you treat them with a combination approach a cocktail of sorts, and we know that Alzheimer’s disease is more than one thing. Anyway, we know that we see amyloid plaques and tau tangles. We Dr. Alzheimer’s 100, over 100 years ago, the first pathologists to look at brain tissue of a person with Alzheimer’s disease. That’s what he saw. That’s what he noted. So he noted two things at the very beginning. So we need to so we might need to do a drug drug cocktail to really really tackled this disease.

MR:  

Very well said.

HR:  

Very exciting too. You know, sometimes we forget the history of all of this stuff, you know, and we can, we can almost come full circle if we’re not careful. Aside from drugs, is there anything else in the pipeline? Whether it be electrical or surgical, old or non medicinal, if you will?

JH:  

Yeah, there, there are some. There’s a, there’s a device approach that we’re aware of that uses gamma ray pulses into to the eyes that help to kind of reset this is some research that came out of MIT. And there’s a company that has been spun off from that. And they’re, they’re in early stage trials, and they’re, they have an interest in also announcing them as a company called Cognito. And, you know, this is it sounds weird, but, you know, they’re Stranger things have happened. And so, you know, yeah, we are very much interested. You know, I mean, it’s, as far as I’m concerned, it’s such an important and big issue that any idea is worth taking a look at, as long as it doesn’t cause potential harm to any participant. That can’t be managed safely. You know, there’s no clinical trial that can be done with with no risk. But you always have to weigh the risk benefit from anything that you that you try.

MR:  

So, you know, actually one of the things that we’re looking at very closely in Alzheimer’s and neurodegenerative diseases in general, but in Alzheimer’s particular is the called the Mediterranean diet. And combined with sleep, changes in sleep to improve sleep, Mediterranean diet methods to reduce stress meditation, and removing people from any potential sources of exposure to chemicals, we’re finding more and more than fine particulate matter. Cotton, you know, in the air is implicated in Alzheimer’s disease. And so everything that we can do to slow and avoid the onset of the disease with doing any harm, as, as James says, you know, the real thing here is first do no harm in this population. So a Mediterranean diet, extra sleep, these kinds of things can be beneficial overall to health, and not cause any harm.

HR:  

The usual suspects, such as exercise, healthy living and healthy lifestyle. You know, right now, what I’m trying to do is find some way to give our different brains.org audience, the people who might be watching this interview, who have family members with Alzheimer’s, to give them some hope. You’ve given them some hope, with the research you’re doing, informing us today about the different markers about some of the drugs in the pipelines and some of the approaches. And, you know, we have to we have to try to give people hope with this. So it’s just not like, Well, too bad. Let’s do it. And the things that make sense, even once one is afflicted are the diet, the nutrition, the socialization, the exercise, keeping things busy joining groups doing different things and trying to change behaviors for the better. I know that sounds you know, like, certainly not as sexy as he has affiliate taken, stops. But…

JH:  

Well, it’s but there is excellent research that’s ongoing now to quantify the and measure what you can achieve. So there are several years ago, a group out of Finland to study called the finger study, I forget what the acronym stood for. But they did. They did. They studied these lifestyle approaches. In a clinical trial type of approach. They had a group of seniors that had the Mediterranean diet, they had regular exercise, social interactions, all that sort of thing. And they compared them to the senior population that just was treated was managed normally. And and they saw improvements in the group that they was retreating. And so this is this efforts being repeated across the world. In the US. There’s a study called us pointer. And in the reason that you have to do it in different countries is every country has kind of different cultural norms, right? So, you know, you may want to, you might want to play a different sport, depending on attack country that you’re in, you might like different foods depending on what country you’re in. So you have to kind of adapt it for each culture. But the idea remains the same. And you know, it comes down to simple thing, you know, what’s good for your heart is probably good for your brain. And it’s also, you know, it’s also what my mother told me, which was, eat your vegetables and go outside and play. These are things that are good for your brain, and they’re also life’s their lifelong things. One of the things that we’ve observed is that people with higher education who have attained higher education, have lower rates of Alzheimer’s and dementia later in life. So that that’s kind of counterintuitive, because we usually are educated as a young person, or child or as a young adult. Why would that impact your brain decades later? Well, it’s because brain health is a lifetime thing. And you shouldn’t just wait until you, you retire to worry about brain health, you need to worry about brain health all along the way.

MR:  

This is important when we think about the two hit model, right, that there could be things that occurred during development, like exposure lead, which come back later to interact with aging. And so you know, we the more we know about these interactions, the more we know about environment and Gene interactions, the better, we’re able to sort of parse out where things begin, and where we can intervene to provide protection by making minor adjustments early that may have big benefits later.

HR:  

Now to our to our audience, who are not at the same level of education, as both of you tell us the big difference, organizationally, between how our research system works at a Boston University, versus said a not for profit, like Lumind, or if they’re the same?

MR:  

Well, we’re supported primarily by NIH grants. So be you as a non for profit. And we seek funding from the NIH. And then we use that funding to do our research. And if we’re successful, we go back and we ask for more funding. So we are a non profit to it’s a it is a non for profit business model. And all of the research is supported by either non government organizations, or the NIH, or some other government organizations like the National Academy of Science or some other organization that might want to give out grants for Parkinson’s, American Parkinson’s disease Foundation, the Alzheimer’s, drug discovery Foundation, these other organizations have grants as well.

JH:  

And so Lumind, yeah, we are supported by donors who maybe care about the cause and carry about dancing in search. So that could be an individual with a wealthy individual, it could be a person of modest means who give us a few dollars. And a call also, as I said, we get funding from for companies as well, because we really believe and engaging with the pharmaceutical industry, because they’ve kind of ignored this population over the years. So we’re trying to build that out. Now, new mind, ideas, see used to provide a lot of academic room. So we’ve kind of moved away from that model, because we’re building a clinical trial network to try to encourage more trials. So we fund 14, largely academic medical centers around the country, that that care for people with Down syndrome. And the idea is that then we can use those centers to do clinical trials in the future. And so that’s kind of how our model works. But it’s a there’s a lot of fundraising. A lot of, you know, hopefully people who again, care about our costs, who liked what we do, are willing to contribute for that.

HR:  

Well, you’re both to be commended for all the work and research you’re doing and helping others. And we here at different brains dot Oregon with our neurodivergent 18 plus year old interns who are doing some research of their own here. And we’re so lucky to have is our volunteer director of research, Dr. Marcia Ratner of Boston University. So, Jimmy, Jim, you better be careful because we’re gonna draft you in here too. Watch your P’s and Q’s. And, you know, I have to say that all of our Different Brains represented by our interns who are all smarter than me, and all their brains are a little bit different from autism, to tuberous sclerosis to epilepsy, and, you know, you name it, we got it. They’re a great bunch. And they’re very appreciative Marcia of the help and guidance you’re given them. And this team is putting out some good research too. So we hope to make a difference.

MR:  

Where were they’re really wonderful to work with, and the enthusiasm is infectious, I guess for lack of a better word, it’s just great.

HR:  

Is there any other any other material that you’d like our audience to know about that we didn’t cover in these sessions?

JH:  

I think one of the for me, you know, if we, I know we didn’t want to talk too much about as your as your home. But Marshall mentioned, the side effect issues. And it’s important that people know that there are this side effect known as ARIA that’s strongly associated with Angelholm. And it requires for people, the FDA put this in the label, anybody who’s on agile home has to get a couple of MRIs, brain MRIs. So if you’re a person who can’t you know, in different brains, if you’re a person that can’t tolerate being in an enclosed space with a lot of loud noise, you should not be on agile home, because that’s the only way we can that clinicians can know if that if if you’re getting Aria. So it’s a really important part of the, the monitoring for the safety of the drug. If you wait for somebody to be symptomatic, that REM means that you have edema swelling in the brain, or you have micro hemorrhaging some brain blood bleed. If you wait till you’re symptomatic was one of those things, it’s, it’ll be really bad. So we want to catch it, they want to catch it early. And usually if you go off the drug, then it results. But you have to be able to detect it early before any any serious damage is done. And that requires an MRI.

HR:  

Thanks for the heads up. That’s an important point. Marcia, anything you’d like to add?

MR:  

Um, that’s, that’s about it. And that’s all I’ve got for today. I think this is, as James said, this is, you know, calling attention to our work is really important. Because people know what we’re doing and that they know where their tax dollars are going when the NIH is funding research like this. And we don’t have, you know, skin in the game. You know, we were not a for profit company. We’re doing this are more altruistic reasons, and hopefully the outcome will be to benefit society.

HR:  

Well, that’s great. Well, I want to thank you both and thank Boston University and thank Lumind, and James Hendrix, Marcia Ratner: you too are wonderful. And I hope this won’t be the last time we get together. But I want to thank you all very much and keep up the great work. Thanks for being here at Different Brains.