This week I am talking to Michael Racke, MD Medical Director of Neurology at Quest Diagnostics. Michael is a board-certified neurologist and formerly editor-in-chief of the Journal of Neuroimmunology, an expert in dementia and brain disorders who has authored/co-authored 200 peer-reviewed studies, book chapters, and reviews on neuroimmunologic diseases, including dementia.
Michael discusses promising advancements in our understanding and treatment of Alzheimer’s disease. He explains how imaging and biomarkers have allowed earlier and more accurate diagnosis, moving from just a clinical picture to actually visualizing amyloid plaques and tau tangles in the brain. We continue with a review of treatments including the removal of amyloid that are now showing delayed cognitive decline and as Michael says there are now over 100 potential treatments are in clinical trials, attacking Alzheimer’s at different stages.
We discuss the challenge of determining the exact relationship between amyloid and Alzheimer’s and the continued work to delineate this and that better diagnosis has also led to the recognition of Alzheimer’s variants affecting different parts of the brain.
Listen in to hear how the timing of treatment is critical; intervening before extensive neurodegeneration allows the best chance of efficacy and the importance of encouraging, lifestyle measures like weight loss and cognitive exercise that may delay onset. As Michael puts it, patients should know diagnosis and dialogue around options is no longer hopeless “Now we have options, and those options are just getting better and better all the time.”
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Raw Transcript
Nick van Terheyden
Today, I’m delighted to be joined by Dr. Michael Racke. He is the medical director of Neurology at Quest Diagnostics. Michael, thanks for joining me today.
Michael Racke
It’s a pleasure, Nick, thanks for having me.
Nick van Terheyden
So if you would, I think, you know, it’s important to get a little bit of context, and you have just a really deep, rich history in this space. Could you give us you know, the highlights of your career, how you got to this point. And, you know, some of the things that you’ve sort of discovered along the way before we get into the detail of the topic at hand.
Michael Racke
So my background is I’m as your I’m a physician, I did neurology training. And when I did mine neurology, it was back in the era, I guess, we used to say we diagnose, we do not treat. But even more importantly, it was very, I’ll say phenomenological. Right. And so one of the things I think that’s become very interesting about how I look at things is from the perspective of how, you know, over my career imaging has dramatically improved how diagnostic testing is improved. And then interventions itself, I’ve, I was actually very involved with some of the development, both preclinical and clinical for multiple sclerosis. But it’s been sort of the same idea in neurology trying to diagnose and these neurodegenerative HERL disorders as early as we can, because the earlier we intervene, the more likely we are to have a beneficial effect in terms of treating a patient.
Nick van Terheyden
So you’re right. I mean, the challenge, especially within the brain, I mean, I think that remains, you know, to pull my Star Trek isms out, you know, undiscovered country, as it were, there’s so much still to understand, we continue to sort of expend a lot of energy. And you specifically mentioned imaging, I think one of the things that really seemed to contribute was functional MRI seemed to be one of the key technological advances that gave us some insights into some of the things that were happening. And obviously, you know, many other areas. Tell us a little bit about the journey, if you would, to the understanding of, you know, the brain and specifically in this case, we’re talking Alzheimer’s, and you know, that disease, you know, from my history, it was untreatable, not understood at all if in any form. Tell us a little bit about the journey and the background to that if you weren’t
Michael Racke
sure. So, you know, like I mentioned before Alzheimer’s disease, when I, when we were both medical students was a clinical pathologic diagnosis. And pathologically, you had to have amyloid plaques and neurofibrillary tangles composed of something called phosphorylated tau in the brain. But I would say from a perspective of like, when we were diagnosing Alzheimer’s disease, that it was clear, first of all, it was clinical, right. And so when you had somebody who began having cognitive problems, what were the problems and if it was somebody who first had aphasia, and then maybe had a dimension, categorized as Frontotemporal dementia, and then with obviously, Alzheimer’s disease, it was sort of these URL, you know, language was certainly preserved early on, it was the recent memories that were impaired. And then that led to understanding of things like PET scans. And interestingly, first, it was not the amyloid PET scans, but it was the glucose metabolism type of PET scans, the same kind of PET scans that we use to try to identify, say, cancer in the body. But instead of seeing hyper metabolism, you could identify types of neurodegenerative disorders by where in the brain, there was metabolites. And then that led to developing radionuclides that specifically could bind to amyloid and so that we had the amyloid PET scan subsequent to that, that you could have any new clients that bounce specifically to phosphorylated tau. And so that all that was the first time that we actually had the diagnosis. Sick people who live with the disorder, right? Because we now could very specifically, say where in the brain the problem was and link that link that to the clinical picture, probably 10 to 15 years ago, people began using biomarkers and specifically in the spinal fluid, right that where you could see that amyloid precursor protein, which is, you know, a protein that’s made on chromosome 21, that when it gets cleaved, one of those peptides amyloid beta 42, is very prominent in the formation of the amyloid plaque. And so, if you are measuring the 40 to a ratio within the brain, or within spinal fluid, or you are measuring sort of come up with algorithms that demonstrated somebody potentially had Alzheimer’s disease. And one of the things that became very clear as well, is that you began to have people that say, for example, look like Frontotemporal dementia, but they had the biomarkers, or the PET scan imaging of Alzheimer’s disease. And so then that was called the frontotemporal variant of Alzheimer’s disease. And I think that becomes relevant. Because now with the appearance of treatments, specifically, FDA approved to remove amyloid from the brain. It’s not so much relevant, do I have Alzheimer’s disease? As do I have a neurodegenerative disorder where amyloid is in the brain? And would repair potential removal of amyloid be beneficial?
Nick van Terheyden
Yeah, so before we start down that track, I want to just backtrack a little bit because this amyloid plaque thing has permeated for a long period of time. And I’ve sort of seen this, you know, up and down in terms of whether it’s just an associated finding, and I’m going to correlate to something similar, but I think people understand relatively well, which is prostate cancer, where the general consensus and I know there’s, you know, there’s always devil in the detail, but many people are found to die with prostate cancer, far fewer die of prostate cancer. So it’s found a lot on histopathology. As a I’ll call it an incidental finding. I’m curious about the relationship between amyloid plaques and Alzheimer’s, is that a similar relationship? Or is it? Do you see a strong correlation? So
Michael Racke
I guess it depends how you look at it. So the amyloid hypothesis is the idea is that amyloid gets deposited in the brain, that somewhere along the line that causes changes in neurons that results in the aggregation of tau in the formation of triangles. I would say that, particularly the autosomal, dominant forms of Alzheimer’s disease, like the the we had talked earlier about the amyloid precursor protein that, you know, mutations in aipp, or pre Civilan, one and two, which caused this drug, dramatic increase in the formation of amyloid do eventually lead to early onset Alzheimer’s disease. But you bring up a very important point, and that is that it’s clearly the task. Much better correlates with eventually neuronal dropout, and then the cognitive findings. Right. Right. And so and then, of course, you have, you know, there are tauopathies, specifically that cause cognitive dysfunction. And then, the other issue is that, and this gets, I think, relevant from that start putting amyloid into their brain decades before they get Alzheimer’s disease, symptomatic Alzheimer’s disease. And so the, you know, why is it that in some people, they do that, and they essentially die and you can, with lots of amyloid in their brain, not much in the way of tau and they were cognitively normal their whole life. Right, as opposed to those people that, you know, had the dominant form of Alzheimer’s disease, of course, also put in tau in their brain But they become cognitively impaired at a much earlier age and die from Alzheimer’s disease, you know, before the age of 50. Right. So there’s clearly, you know, there, there are clearly other factors that sort of play into it. And I think the reason there was so much interest in amyloid one is because it sort of has given you this marker, that perhaps gives you a window of opportunity to do something about it. As opposed to some of the later markers were when they by the time they come up, it’s, it’s clear that already there’s significant neuronal drop out, and it’s the neuronal drop out that we can’t really reverse. Right.
Nick van Terheyden
So why is it fair to say that it’s still muddy waters in terms of you know, those relationships or not? Is it Do you think there’s a clear line to be drawn between the two?
Michael Racke
Yeah, so that I mean, there’s, I would say, there’s still a little bit of muddy water, I would say, you know, for, for the people where they say, you know, we removed amyloid and it didn’t work, they would argue, okay, that’s going against the amyloid hypothesis. And then there would be people who would say, Yeah, but they did. Those are many of those trials, had poor selection of patients, the early Alzheimer’s trials, that 30% of patients didn’t even have Alzheimer’s disease, right. And so those trials are sort of doomed to failure from the get go. I think, you know, it’s, it’s also from the perspective if, if you already have had a lot of neurodegeneration, and then you remove the amyloid, you demonstrated you could remove the amyloid, but it was too late, the the the neuro degeneration had already occurred. So in the cognitive function, I would say that the recent studies and the studies that you know, that we’re seeing data, for example, to Nana Mab, which hasn’t been FDA approved, but I believe is on the docket to get approved, potentially, in February. It’s clear that, you know, as these studies go forward, we’re doing a better job of patient selection. And so the treatments seem to show a better clinical effect. Right. And I think one of the things that’s going to be very relevant is this idea that, you know, can we actually identify patients way before White who are still cognitively normal, and intervene? Those are studies that are currently ongoing. But I think that’s, that’s where the excitement is, in some sense in the field, right?
Nick van Terheyden
So for those of you just joining, I’m Dr. Nick the incrementalist today I’m talking to Dr. Michael Rocky. He is the medical director for neurology at Quest Diagnostics. We were just diving deep into the Alzheimer’s history, some of the background to the science, the discoveries around amyloid tau tangles, you know, correlation causation, you know, in fairness to everybody here, I think, deeply complex subject very hard to give it full credence in, you know, limited amount of time. But suffice to say, I think what I gathered from you, Michael, is that, you know, there’s genuine potential, I think there’s clearly been some, I let’s call them missteps. You know, I dislike the term failures, because I think we can always learn from some of the studies, even if we don’t show benefit, particularly if they’re poorly designed, or they don’t select their patients or their endpoints appropriately. It sounds to me now that we have both, at least a smoking gun. There’s, you know, there’s multiple smoking guns potentially. And I think also some treatment options available today. Is that a fair summary of where we are?
Michael Racke
Yeah, I would say that is a fair summary. I think the you know, it’s interesting, I don’t want to get into the controversies of some of the FDA approval, but one of the things that’s clear, is, you know, even with the approval of magic Hannah Mab, then to go to law Academy. Hopefully soon to that event. You see significant improvement in patient selection in the when we actually treat the patient and then subsequently seeing a delay in cognitive decline, right. And, you know, I think the thing that’s exciting is that I mean, there’s like 100 treatments that are currently in clinical trial, right. And there are just constantly improvements, not only in how we diagnose the disease, but also how we monitor, both by biomarkers as well as by cognitive testing. So I mean, it’s really, it’s really an exciting time.
Nick van Terheyden
Yeah. And to that point, you know, on the basis that there’s some treatments, and even prior to treatment, I did hear one of my favorite comments around Alzheimer’s, you know, particularly with the gene identification, because it’s not a one to one relationship, you know, what’s the benefit of that? And one friend of mine said to me, well, I’ll just play more Sudoku to try and, you know, preempt any early onset of Alzheimer’s, and, you know, a little bit flippant, but ultimately, knowledge is always power. And we’re now at this point where we have some treatments available. But the diagnosis, still somewhat challenging, but there are some new opportunities around that. And, you know, perhaps I’m going to call it less invasive, you know, you talked about it, especially from a monitoring standpoint, if we’re going to understand if these therapies are actually working. And I think, you know, much like cancer when we identify cancer, particularly with, you know, the traditional means of imaging, and we see a nodule, by the time you see the nodule, you’re talking billions, if not trillions of cells, I forget what the numbers are, but, you know, many, many weeks, months, even years back that was forming, but we don’t see it, but maybe we see those biomarkers. And that’s a lot of the advancements, some of the insights. Tell us a little bit about what’s happening in that space, if you would.
Michael Racke
Sure. So, I think one of the things that was clear, is that we developed biomarkers to identify both the fact that amyloid is being deposited into the brain and that you can identify certain species of phosphorylated tau, I would say the, the big ones are p tau 181, to 17, and 231. But there’s clearly other ones that are also in development. p tau 181. It’s kind of interesting. It’s, it seems to be pretty strong for Alzheimer’s disease, but it’s also been seen and another very scary disorder, a mild trophic lateral sclerosis or Lou Gehrig’s disease. Some of the P towels had been seen in some of the other tauopathies. And so, you know, one of the things that I think is important to recognize is the ability to characterize Alzheimer’s disease or neurodegenerative disease, and then how one tries to potentially intervene. And, you know, it gets to the point that Alton, you know, from my perspective, you know, Alzheimer’s diseases, dementia, but not all dementia is Alzheimer’s disease, but also then from the very specific perspective of using biomarkers to understand the pathophysiology and then say, Can I actually interrupt this pathophysiology in a way that potentially is beneficial? And I think one of the things that’s very exciting is that, you know, certainly both by PET scan, we’ve been able to demonstrate that these monoclonal antibodies can remove amyloid from the brain, but that you also then see the downstream effect that there’s a lowering of some of these P towels, right? So that sort of gets back into this all you know, the the amyloid hypothesis, is amyloid really, somehow fundamental in the formation of an aggregation of p tau. And then I think the other thing is that there’s other biomarkers, some of them not specific for Alzheimer’s disease, some of them can be used in other disorders, but that, you know, we look at something like neurofilament, like that clearly increases as we get older, it increases much more quickly if we have a dementing illness. It also increases in for example, if somebody has an attack of multiple sclerosis, so it’s, it’s not specific for Alzheimer’s disease necessarily. It’s much more specific for damage to neuronal axons, and on the flip side, a molecule like glial fibrillary acidic protein is a molecule that, you know is made by astrocytes and astrocytes, I’d say are like the fibroblasts of the brain supporting tissue, but they also cause the scarring, that appears to be a good marker. And as for looking at the treatment effects for some of these monoclonal, it’s also been a marker to look at scarring in the brain and diseases like multiple sclerosis, perhaps a defining marker for secondary progressive MS. So we’re beginning to identify markers that allow us to better see where a patient is on the Alzheimer’s continuum. And I suspect one of the things that seems very clear as well, you know, is that when people advocate for these wellness, right, and how good are we at making effects in these neurodegenerative diseases, one of the things we see is that if we lose weight, exercise more, you’re talking about doing good Sudoko and exercising the brain, that what we see is that not only does that seem to push back the onset of the political onset of Alzheimer’s disease, you see some improvement in the biomarkers as well. Right. And so I think that those are all very positive signs that we are making progress against some of these very devastating neurodegenerative disorders.
Nick van Terheyden
Yeah, so in the limited amount of time that we’ve got left, if you word Could you try and summarize what a patient should be thinking about? You know, we’re, we’re all approach, you know, ages is inevitable. How do people approach this? How would you advise people to approach it? It’s obviously a rapidly changing landscape. There’s major advances, there’s clearly opportunity. And, you know, I think like most diseases, my sense is, if you get to it earlier, you’ve got more of an opportunity to deflect the course or even be preventative. How should they approach it? Right.
Michael Racke
So I mean, I think that, certainly, for people who have family history, and it could be family history for late onset Alzheimer’s disease, right? If you, if I have a bogey for running in my family, that’s more more likely. But it seems like I said, it seems very clear now, this idea of wellness, that, I think that seems to me to be the big thing going forward. And that certainly if you or your partner notices, early signs of cognitive dysfunction, that that gets evaluated as soon as possible. Because, you know, whereas when we were last I mentioned before, when we were students, we didn’t really do anything, but now we have options, and those options are just getting better and better all the time.
Nick van Terheyden
So as I think about this, you know, long course, in this history, I mean, many elements of progress in terms of understanding the disease, the underlying, physiological, genomic, even, you know, I would suggest proteomic elements of this and what contributes to it, I think we’ve made tremendous advances, we’ve obviously made advances in terms of potential treatment. I know there’s, as you describe some controversy around that. But, you know, as we start to understand this more and better, we’ve got more opportunity to understand what’s actually working, especially if we can correlate the biomarkers that you’re talking about that we’ve started to identify, and can I imagine test for and use those as monitoring or yardsticks for progress of, you know, either the disease or broadly for any of the treatments? And then, as we start to understand this more, obviously, that opens up the door potentially for more treatment availability. That gives people hope, because I think, certainly, in my era, and I think you and I described this, it, I don’t want to call it hopeless, but it felt a little bit hopeless. When you had that diagnosis. It was okay, you know,
Michael Racke
and I think that’d be an accurate statement. Well,
Nick van Terheyden
I accurate unfortunately. But you know, now that’s potentially not the case. And that’s great news, some exciting times, unfortunately, as we do each and every week. We’ve run out of time, so it just remains for me to thank you for joining me on the on the show. Michael. Thanks for joining me.
Michael Racke
Well, thanks for having me, Nick. It was a pleasure.
