#399 ‒ The evolution of Alzheimer's disease and dementia care: how early detection, personalized treatment, new therapies, and a multimodal approach are changing the landscape | Gayatri Devi, M.D.

[Music] Hey everyone, welcome to the Drive Podcast. I'm your host Peter Atia. This podcast, my website, and my weekly newsletter, all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription. If you want to learn more about the benefits of our premium membership, head over to peteratia-md.com/subscribe. [Music] My guest this week is Dr. Gaya Devi. Dr. Devi is a neurologist and psychiatrist specializing in memory disorders, cognitive neurology, and women's brain health. She is the founder of New York Memory and Healthy Aging Services, and a clinical professor of neurology at Zucker, Hofstra, Northwell School of Medicine. Her practice spans the full spectrum of Alzheimer's disease from asymptomatic high-risk individuals through advanced dementia, and she is known for a personalized multimodal approach that integrates biomarker, guided diagnostics, anti-emloid therapy, hormonal factors, and lifestyle interventions. I've wanted to have Dr. Devi on the podcast for a while now, because the field of dementia is changing rapidly. For a long time, Alzheimer's disease was viewed as really kind of a one-way decline, diagnosis with very little room for nuanced intervention. But she takes a very different approach, one that is highly individualized, focused on early detection, careful risk stratification, and matching the right combination of treatments to the right patient. In this episode, we talk about how to think about dementia as a spectrum, including Alzheimer's disease, but also vascular dementia, Louis-Baudi dementia, and many other mixed presentations in between. As opposed to discrete diseases. The evolving biology of Alzheimer's disease, including amyloid, tau, neuroinflammation, and why pathology does not always map neatly onto symptoms. How she evaluates high functioning patients with very subtle cognitive changes and how she thinks about biomarkers, apoe for risk specifically, and testing asymptomatic people. We talk about anti-amyloid therapies, which have become very controversial, although slightly less so today than when they were initially released, including Lecana Mab and Decana Mab, their risks and benefits and her approach to reducing side effects, including the most devastating side effects which we talk about. Why some patients with Alzheimer's disease may stabilize or even improve with a personalized multimodal treatment strategy, the overlap between Alzheimer's disease, vascular dementia, and Louis-Baudi dementia, including why Louis-Baudi disease is often confused with Parkinson's disease, the relationship between menopause estrogen and cognition, including her specific concept of menopause-related cognitive impairment, and finally, how early detection AI-assisted monitoring, neuroinflammation, targeted therapies, and more personalized treatment may reshape the future of our dementia care. So without further delay, please enjoy my conversation with Dr. Debbie. Gaya, so great to be with you today. Very excited to talk about this. It's a topic that we've discussed a number of times on the podcast, but unfortunately, there's always a lot to talk about here. And I think your physician that of course is near and dear to our heart in the practice, we co-manage a number of high-risk patients, and you know, I've just always been impressed by the way that you have taken a very personalized approach to managing this condition, but I just want to let folks get to know you a little bit better. So you're both a neurologist and a psychiatrist, is that correct? That's correct. I mean, I'm boarded in multiple specialties, neurology, psychiatry, brain injury medicine, pain medicine, and behavioral neurology, but my sub-specialty is really memory disorders primarily from a neurological perspective, but all these other areas allow me to better handle people with cognitive impairment. I'm just kind of curious as you think about the evolution of your career when you started, which is obviously not that many years ago, you're still quite young to where you are today. What has been kind of the biggest shift in your understanding of the demanding conditions that we're going to talk about today? I think two things, Peter, one, that over the years of my practice, I've come to realize that pretty much all demanding conditions and particularly Alzheimer's disease can present variably depending on the person who has the condition, and also depending on comorbidities. So there really is a spectrum aspect to Alzheimer's and dementia, which people don't recognize. They think of it as an all or nothing disease, and that's not true. Much like autism, it really can span the spectrum from very mild impairment that doesn't get worse to severe impairment that kind of deteriorates rapidly. That's number one that dementia are really a spectrum disorder. And number two, that what's really exciting to me is I feel like I'm in the field now almost as if I was an infectious disease doctor who is practicing medicine before an after penicillin was invented, you know, or discovered. Sorry. So basically that there are now so many different ways that we can treat dementia's we can personalize our treatment. We can give each person the right cocktail, if you will, of medications that would best benefit them. And we now have drugs that can alter the course of the disease, which is absolutely to my mind, fantastic. You still have a ways to go, but I feel like we're on the threshold of something really grand. Well, that's probably the thing I want to talk most about today, but I I think there's some groundwork I'd love to lay to bring the listeners along with us before we get into both the treatments, but also the way in which you personally kind of manage some of the risks. So we're going to talk about some of these risks and then the various treatments around them. But before we do that, let's go back to kind of what you opened with, which is that we're not dealing with binary diseases. It's not like you have vascular dementia or you don't or you have Louis body dementia or Alzheimer's disease or you don't. Can you go a little deeper into this idea of what the spectrum of these diseases look like and maybe for the purpose of this first question, let's limited just to Alzheimer's disease. So maybe define Alzheimer's disease within the broader context of dementia. I think there's probably still some people who use those terms synonymously, even though they're not. And then within Alzheimer's again, walk us through the different subtypes, if you will, and maybe how a clinician is able to arrive at that diagnosis. Right. So dementia is the umbrella term. So a de mentation of the brain. And that means that there is loss of connectivity between the brain cells that results in a loss of function. And it's a progressive condition. That's dementia. And there are several different types of dementia, Alzheimer's being the most common. And what Alzheimer's is defined as is a loss of synaptic connections or synaptic connectivity that results in a loss of function that is driven by the presence of extra neuronal amyloid flags. Intra neuronal or intracellular tangles, neurofibreillary tangles, and increasingly what we now know to be inflammation in the supporting microglial cells and other glial cells of the brain substrate that cause cognitive impairment that progresses. So the question is, how do you make this diagnosis in a person? And you know, that's really difficult because you have to really be have a high index of suspicion, particularly with people who are very intelligent, people who are very functional, people who are able to compensate very well. So that you can have someone who has moderate pathology and even severe pathology and they can still perform very well in many areas because they have a good brain reserve. They have a resilience in their brain that prevents the kind of cognitive and functional deterioration that someone who has less reserve and less brain resilience doesn't have a good sense of the brain reserve. have. And there are many different subtypes of Alzheimer's disease, depending on the part of the brain that's affected. So you have, you can have an Alzheimer's disease that primarily affects memory versus Alzheimer's that can affect more the visual spatial system. So depends of the, on the area of the brain where the pathology tends to predominate. And it also depends on secondary conditions, cool morbid brain conditions that are present, such as Louis body disease, TDP 43 pathology, or gerophilic brain disease, all of which can inform how the person presents. So when you're looking at Alzheimer's disease, you want to look at, first of all, you want to establish that the person has these plaques and tangles. And that's something we can get into later because there are two groups of thought on that. There are people who say, well, you can just have biological indices that say that a person, you can diagnose Alzheimer's just based on biological biomarkers alone versus another group that says, well, no, you need biomarkers plus clinical symptoms. You need biomarkers plus functional deficit to make the diagnosis. But the biomarkers are really amyloid, tau, and increasingly neuroinflammation. Okay. A few things I'd like to unpack there. But maybe I actually want to start with a more basic question, which is, we will get to obviously talk about apoe, the genotype, which is probably one of the most common genetic predisposing factors, although not the strongest. And maybe we can even spend a minute talking about the other genetic conditions that are more dispositive in their prediction of a person developing Alzheimer's disease. But pathophysiologically, what is the order of operations? Stayed in another way, what starts this process? Does it start with the inflammation? Does it start with the deposition of amyloid? Does it start with the tangles? Is it different in every person? Is it different by location in the brain? Maybe talk us through that a little bit. So generally speaking, used to be thought that really amyloid was the first abnormality that begins in the brain up to two to three decades even before the onset of clinical symptoms. But now we're beginning to understand that changes in the inflammatory pathways may predate amyloid deposition by quite some time. So it may be that first neurological changes, then amyloid, and then eventually down the road, tau, and that ultimately causes synaptic dysfunction, where the synapses, the connections between the nerve cells start to go awry and the person then develops cognitive changes. And that process takes decades. So the whole point, I think, with Alzheimer's is another dimension is if you can intervene early enough, even as early as your 30s into your 40s, by incorporating anti-inflammatory, methodology, anti-inflammatory activities into your lifestyle, and perhaps you can prevent the whole cascade from being triggered. On that topic, one of the things we've become much more aggressive in our practice around is managing two viruses in particular, herpes simplex virus and varicella zoster. Now the data appear much, I think the data appear stronger for the management of varicella zoster through the use of a shingles vaccine in individuals who have been previously infected, which of course, at this point of the time, your 50s is virtually everybody. And so presumably the observations that we see that there's a significant reduction in the risk of dementia and Alzheimer's disease in people who have been vaccinated for shingles and people who have HSV treated suppressively versus those who don't. The thinking is that this works through an inflammatory pathway. What can you say about any of that? Yeah, I really think there's something to be said. I think neuroinflammation is going to be the new frontier in terms of how we're going to deal with and even prevent entirely Alzheimer's disease. I have, for example, like two patients in my practice where the sibling is riddled with Alzheimer's, but these two patients have severe neuro-analogical disease that they've been treated with aggressively for decades. And neither of them have a lick of Alzheimer's pathology. It's quite impressive. So I think there's something to be said for this kind of treatment with an exposure to various viruses that have a predilection for the brain and the central nervous system like the herpesostatic virus, for example, that causes shingles. Sorry, just to clarify the case you presented there, are you saying you have three siblings that are genetically comparable? I mean, meaning like they would all have the same APOE phenotypes across them. They're three fours or four fours or whatever. One of them has disease. The two that do not have a deficiency of their immune system that renders them less susceptible to mountain immune response. So I have two pairs of siblings. So in each of which one sibling has significant Alzheimer's and the other sibling doesn't, which is particularly remarkable in one case because that person has two copies of the APOE for allele, which puts them at higher risk. In fact, definite risk for developing Alzheimer's and that person doesn't even have any amyloid, not even a touch of amyloid in their 70s. So it gives you pause. It makes you think, well, what is it about this person that protects them? And are you saying that they have a known immunologic condition that is reducing inflammation or you saying that's the hypothesis potentially? That's the hypothesis. The hypothesis is and that the fact that they've been treated with various drugs that somehow modulate the immune system may have had maybe factors here. Again, it's speculative, but it's certainly worth thinking about. Yeah. The other thing that I would say that lends some credibility to this argument. And again, unfortunately, we're largely stuck relying on epidemiologic data as opposed to clinical trials, although there are trial data on some of the vaccines, is the relationship between gingerval health and dementia, which again points to this idea that you have an area that is in very close proximity to the brain. And, you know, as anybody knows who's listened to our podcasts on dental health, when the gums are inflamed, it wreaks havoc on the body through an inflammatory pathway. And so the brain would obviously be highly susceptible to that. So again, I think all of this makes sense. Yeah, I totally agree. And to your point, even the entire gastrointestinal system, you know, the internal lining gets replaced what every two weeks the entire lining does. So you've got to think what happens in that process and how that drives, you know, that changes with different immunological conditions. So talk to me about how you evaluate a patient. Let's maybe take a step back and talk about your practice. So our patients coming to you more commonly being referred by another physician or patients coming to you directly because they find out about your center. And they say, look, I, you know, me or a loved one are concerned about some evolving symptoms. But basically, how are patients finding their way to you? And what is your process of evaluation? We have, I've been in my practice on the upgrade side for 26 years. So over this time, there's a large referral base of physicians who refer to me. I also have kind of developed a niche in terms of the evaluation and treatment of physicians and other professionals. So they seek me out. They read an article on an journal or something along those lines. And then of course, referrals through families and friends. The one thing I will say about our practice is most of our patients are highly functional. They're still working many of them and they want to stay working. And my great joy in my in these years is that I've been able to help them achieve that goal to be able to stay functional and useful to the society and also have a sense of agency for themselves. So the thing, the challenge with all these patients, especially the high functioning ones, is that they are extra ordinarily, their brains are extraordinarily smart, compensating. So a lot of the testing that we do has to be fairly rigorous in order to uncover the problems that such patients might have. So if you did like what people routinely know, which is the mini mental status exam or the MOCA exam, many of these patients score a 30 or 29 or 28 well along into their condition, even 10, 15 years into their condition because they are so adept. They have such great cognitive reserves. What do I mean by cognitive reserve, the ability of the brain to maintain a large number of connections and to be resilient to disease, such as Alzheimer's. So once we put them through, so first of all, we do a very meticulous, general history, including history about immunological conditions, past exposure to shingles, things like that, a family history, and then after that decide on the kind of testing we want to do, which often involves a cognitive testing, which takes several hours. We often will look at the electrophysiology of the brain to see if there's any evidence of early slowing, look at brain blood flow using transcranial Doppler to see how much blood close to different areas of the brain. We will do specialized exams, imaging exams, such as MRIs using special techniques so that we can evaluate the different brain regions, such as the hippocampus, the pridal lobes. So we can see if there's differential changes there, early changes, and oftentimes, especially here in New York, we're able to do amyloid scans and people that were worried about and tau scans, which measure brain levels of tau, which is the other abnormal protein that's associated with Alzheimer's. And sometimes we will also do what are called DAT scans, which are scans looking at dopamine levels in the brain, which also help us to differentiate if there's another process going on. So it's a fairly rigorous series of tests that's tailored to each individual person, and of course, of laboratory testing, looking at APOA, APO Little B, inflammatory markers, and obviously the APOE genotype, and certain patients where there's a history, family history of early onset Alzheimer's, we do do early onset genetic screening to see if there's a particular gene that's abnormal. How routine is the use of a lumbar puncture? Is that something you would do in everybody, or have the, has the robustness of the current blood-based biomarkers for AB 4042 and PETO displaced a lot of the need for lumbar puncture? So I am kind of, I think I'm old school with the blood-based biomarkers. I definitely think they are the future, but I'm not sure they are already the future. I don't, I feel that they are standardized against amyloid for the most part, amyloid scans, and I'm off the opinion that they would probably need to be standardized against both amyloid and tau, because so many of us in our 70s and 80s have amyloid and will never develop Alzheimer's. So I tend to pretty much in anyone that I'm concerned about with Alzheimer's, I will do either tau and amyloid scan or a spinal tap. The advantage to the spinal tap is it's less expensive, and you also are able to detect very early changes in tau, whereas the tau PET scans traditionally don't really pick up early changes in tau. The disadvantage of course is no one wants to get a spinal tap, although may I just say that all the women who've had epidurals to have children have effectively had reverse spinal taps, you know, they've had anesthesia injected into their spinal cavity. That workup sounds incredibly extensive on average since you're managing this as patients who are outpatients. You can't do everything you just said on a day, I'm imagining. So is that for a motivated patient? Is that a week, two weeks worth of interventions? So we have patients come in from around the world or from different parts of the country and they're just here for testing and in evaluation and we're able to pretty much schedule everything over two to three day period. Okay, that is an exhaustive list of tests. I'd love to kind of walk through the contours of how you piece together results and start to come up with what the archetypes are. So in other words, once you have all of those tests back, how do you start to say, this is the pathology? So let's call it by disease. So I think you're on an Alzheimer's pathway. I think you're this far along on the pathway and I think it's of this variety. Does what you see in one snapshot give you a sense of velocity? Or can that only be determined over a time course where you repeat the evaluation a year later, look at the change and say, this is a slowly progressing versus a rapidly progressing condition. And basically, how do you take that information and then create a treatment plan? That's such a great question. You have to marry the symptoms that the patient has, the time period over which the symptoms have occurred, how all the personas, their cold morbidities, whether it's high blood pressure, obesity, cholesterol, high cholesterol, and other brain cold morbidities. For example, how many strokes they've had, where these strokes are located in the brain, which occurs in quite a large percentage of patients with Alzheimer's as they have concomitant, cerebral vascular disease. And then you look at the test results, how many copies of the APOE 4 allele do they have? Or do they have a presenal and one mutation, which is 100% associated with Alzheimer's, usually early onset Alzheimer's disease. You also want to look at their cognitive scores to see, is this person has an overall intelligence at the 99th percentile, but their language scores, their ability to come up with words, is at the 10th percentile. This is somebody I'd worry about because it means that they're progressively losing their language skills and they're having trouble communicating. And let's say they're working in a job as a lawyer that it may affect how well they're going to be able to function. And that's one of the ways I assess in a single time point, how much of a change has occurred. So someone who's overall ability, the 99th percentile visual spatial skills of the 10th percentile language, suppose it's 10th percentile, I worry that this person's decline quite a bit, but they're compensating overall. And maybe the next, the following, the ensuing year might be a year where they, they're losing quite a bit of function. So this might be someone where you want to be more aggressive about treatment. You have a patient who's having problems with language and they have just in that area, their blood flow is much reduced, or they have some slowing in their EEG, which is worrisome even if they look clinically fine. All those things go into all those different facets of their evaluation go into my final determination of how much of each condition, often it's very rare that the person just has primary Alzheimer's alone. They'll usually have Alzheimer's plus, Alzheimer's plus a little bit of stroke, Alzheimer's plus a little bit of hydrocephalus, Alzheimer's plus a little bit of TDP 43 pathology. So you want to kind of put that all together and see how much each area is being affected. Interestingly, if it's only memory that's being affected, that's actually a better prognosis for patients than if it's primarily language that's being affected because we have data to show that the trajectories, the rate of progression varies across depending on where the pathology is. And then I'm not, I'm one of those people I think who's very, very, very averse to staging Alzheimer's. I am not, people often will say me, well, what stage is this person in? And I usually say, listen, this person is at stage zero as far as their ability to communicate, but maybe in memory, there are that stage three or four and maybe in language, they are in a different stage. So you really want to look at the person in all their different functional domains and stage them on their different domains. That helps you better than just giving an overarching stage, which I find to be very reductionist, simplistic and does it deserve us to both the patient and the family. I want to ask you a question that I am positive you get asked every time you go out and someone finds out what you do for a living, which is what explains the fact that I might be seemingly in perfect neurological health and yet I find it very difficult to remember names of people who I know. And I don't mean like no very well like my wife or my kids, but like a person who I've met 30 times, I might see them for the 31st time and it might take me a full minute to remember their name. So people ask me this all the time because they experience it and truthfully I observe it in myself a number of times and it's not just a name of an individual. It could be, I don't know, like the name of a city or something like that. It just happened to me the other day. day, I couldn't remember Ibiza. I was like, what is that place in Spain again where everybody goes to party? And it literally took me, it felt like an hour. It was probably 15 seconds, but it was an eternity to come up with Ibiza. Like, I don't know how I could forget something like that. So again, I don't believe that I have Alzheimer's pathology, but what explains this phenomenon of occasional delays in acquisition of names? This is your right. One of the most common questions that I get asked and one of the most common requests, will this treatment help me remember better, particularly Nays. And I always say, get used to calling people darling and dear, become more Southern, you know, because the truth is names are inorganic bites of information. Our brain is trained to remember things organically. So a name is really a neologism. It's a made up thing. It doesn't have very much meaning. And we are now, particularly in modern times, obviously, inundated with Nays. Whereas 100 years ago, there were very few names that one had to remember. There are certain people who have a proclivity for remembering names, politicians, for example, someone you might know who never forgets a name. But the vast majority of us are brains are not meant to remember an endless amount of names. We really maybe, I mean, some people speculate that maybe we're only supposed to remember 150 names, which is very, a very small amount. I would say that the majority of us have access to most names. And it will, it's not to me a viable thing to try to recover as we get older because it's an effort that I think is doomed to failure. The other issue, which I think is more problematic, is the ability to recall common nouns. To remember, to call something a chair, to say, well, that's a book. I want to know the five different ways you can say green, you know, short truths, toe, toe of hunter green, etc. Those kinds of things, if you're beginning to have trouble coming up with finding words for that, a finding words is supposed to trouble finding names. That becomes more of a problem because that kind of memory is much more housed in the part of the brain, which deals with facts as opposed to names, which I think, unless they are well rehearsed, like the names of your family members are much more episodic. Their names, their names are more like episodes, tryable, things that happen that have a specific time and place. What did I have for breakfast? What did I eat yesterday? What color was the jacket of the person I saw two days ago? None of those things matter. Our brains are designed to forget most of the things we're exposed to most of the time because that's how our brains function. And all these episodes, all these times where we have little micro-memories on a daily basis, millions of micro-memories. If we kept them in our brain, we wouldn't be able to function. So evolutionarily, we're designed really to forget most names and most episodes. That is very reassuring to hear because even though that has been my intuition and that is how I have generally counseled patients when asked this question, there's always a tiny part of me that gets worried when I can't remember one of these names. Let's talk a little bit about now the evolution of treatment. Actually, no, no, there's one question I want to ask you about before we get there. We haven't alluded to it yet on this podcast, but it's been discussed on other podcasts and we've written about it. And I think many people listening may be familiar with this fact. But there is a significant difference in the prevalence of Alzheimer's disease between men and women. There are lots of speculations as to what those are. I have my own thoughts. I'd like to hear you sort of provide your views on maybe what could be driving that and anything else that is different beyond just the top level prevalence. There must be some biological or nuanced differences in presentation and things of that nature as well. Right. So let's not forget that compared to 150 years ago to now, our life expectancy has nearly doubled. We've gone from an average life expectancy of 50 plus 50 52 years to now 70 late 70s early 80s. And women 150 years ago, generally were dead by the time they reached men of pause, which is the time period when we stopped making estrogen. And we now know that estrogen receptors co-localize in the brain, particularly in different parts of the brain that deal with memory like the hippocampus. And estrogen, the presence of estrogen drives and keeps drives synoptic sprouting in the hippocampus. Dominique Turan-Alarond at Columbia did some of the early work in this. And Barbara Sherrin at McGill did quite a bit of work in terms of what happens to women who go through surgical menopause, who've had, you know, who suddenly stopped making estrogen. And their deficits and memory deficits, they start to have trouble with short term memory, they have trouble with executive function, they have trouble with recall with word finding. This looks identical to the early stages of Alzheimer's disease. So imagine someone in their 40s who may not realize that they're going through menopause or perimenopause because it's a very gradual process and they start to notice these changes, then they can. And I actually have this, I have patients in my practice who've been misdiagnosed with Alzheimer's disease and other dementia, who really only turned out to have menopause-related cognitive impairment where they have findings that are identical to what you see in early Alzheimer's disease that are objectively seen and that can be treated with warmer replacement and if that's not possible with various other interventions. Now why is it, is it because of this lack of estrogen for the pretty much half their lives or third of their lives that women are at higher risk? That's possibly one reason. It could also be because men die quicker from cardiovascular disease than women do, women tend to survive more after cardiovascular insults and therefore whenever you have any kind of risk factor for cardiovascular disease, disease that also puts you at higher risk for Alzheimer's disease. The two conditions are so intertwined that years and years ago in 2002 there was a paper that said, is Alzheimer's stroke, published in the journal circulation because if you look at the risk factors for Alzheimer's, every single one is also a risk factor for stroke and cerebral vascular disease. So women surviving past a time period where men die may also put them at higher risk for Alzheimer's. There's certainly a huge difference in immunological susceptibility to illnesses between men and women. There's a big difference in multiple sclerosis risks between men and women. There's a big difference in various other rheumatological conditions between men and women as lupus, erythematosis. So there may be immunological factors that we don't yet know that are driving a higher risk in women. Reason being, and of course people always say, well, women live longer, maybe that's why they're at higher risk, but we do know that even when you adjust for that increase, you know, life expectancy of women, they still are at higher risk. And the other interesting thing about women who present with Alzheimer's, who have gone, is that they present differently. Women often will present with depression. They present with withdrawal. They often have more language difficulty problems than men do. Men present more often aggression with agitation and so the presentation is different as well. And what about the pathologic findings when you get right down to the assessment? If you took a man and a woman who would ultimately turn out to both have Alzheimer's disease, are you going to see differences in the patterns of amyloid versus tau versus any of the other markers that you're looking at as sort of standard markers? Generally speaking, not Peter. Generally speaking, it's very hard to differentiate between the sexes based on the biomarkers or based on the differences in testing. But certainly, I mean, in terms of their presentation, I would say very strongly that women are far more likely to present with depression. And also women who will present with Alzheimer's tend to generally have gone through earlier menopause, tend to generally not have been on Homer replacement. Yeah. And unfortunately, as we sit here recording this in 2026, we're still sort of dealing with that problem because you again have that generation of women I refer to as that lost generation that were with, you know, denied HRT following the WHOI in 2002. And so these are probably the women that are coming fully into the consequences of that at a higher rate because these are women that would now be in their 70s having never had hormone replacement therapy, which again is I'll get off my soapbox before I even get on it on that topic. We didn't actually, maybe just for the sake of completeness, finish the swing fully. My bad, I took us away from it on some of the top level biomarkers. So we mentioned them, but maybe give folks a sense of what you're looking for. So I think people nowadays, meaning patients themselves are even requesting, hey, you know, Doc, can you look at my AB 4240? Can you look at my PTAO217? Can you talk about the most common commercially available validated assays and what the levels mean? And also, I'd like you to, after that, give us your point of view on the utility or futility of testing asymptomatic people. May I talk a little bit about the differences in diagnostic approach here? Absolutely. Okay. So I actually tell you a story. I saw a patient in the early part of last year who just had, you know, as a high functioning man who had in his seventies kind of vaguely wasn't feeling well, ended up seeing a neurologist who I really respect at an academic center here in the city and got tested for, he actually happened to get the quest testing for 80 to test to see. And it turned out he had abnormal levels of a beta 42. And therefore was diagnosed with Alzheimer's by this neurologist and he came to me for a second opinion. My feeling was, you know, after talking to him, I wasn't really convinced that he had really cognitive impairment. I thought he felt a little slow, a little sluggish. Maybe there were physical issues. And be that as of May, we did amyloid scan and his scan was negative. So for about three weeks, he had taught he had Alzheimer's. He didn't have Alzheimer's just based on the scan along. So I'm saying this as a cautionary tale to say that you want to be careful making a diagnosis of Alzheimer's with just the blood tests alone. I mean, there are certain blood tests, the, the lumi pulse blood tests, the precipity blood tests, the quest AD blood test, the C2N assays. But all these are generally all the blood tests are standardized against for the most part. I think there are a couple that aren't. But the ones I mentioned are all standardized against amyloid beta pathology on PET scan. So because amyloid is present, so if you take all, all people in their 70s, community dwelling people and you image them, about 25% of us will have amyloid in our brain. If you take people in their 80s and you image them, about 30 plus percentage of us will have amyloid. And by the time you get to 90, about 44% of us will have amyloid without symptoms living in the community. So if you're going to standardize a blood test and say this blood test is sensitive for picking up Alzheimer's and it's specific for Alzheimer's. In other words, when it's positive, it means it really is Alzheimer's and not another condition. But you're validating it against an amyloid PET test with PET scan. You see my problem there is that because amyloid is positive in so many people as we get older, many of us without any clinical symptoms, what does this really mean? And so this is now a critical juncture, I think, in terms of how we diagnose Alzheimer's because there are two groups that have different approaches to diagnosing Alzheimer's. That is the Alzheimer's association criteria for diagnosing Alzheimer's, which diagnosis Alzheimer's primarily based on the presence of amyloid, whether it's in the blood, whether it's in the brain. And there's the international working group, which is mostly your PN, but international, a member of the national institute of aging is a part of it, a few American major centers are a part of it as well. That group feels that there are too many people who have amyloid so that when you make a diagnosis, you really want to be sure that you have amyloid and tau and symptoms. So it's a clinical biological condition rather than a primarily biological condition. So I'm careful about testing people who are asymptomatic unless they have a family history. So for example, I have a young physician in her 50s, both her parents had Alzheimer's, confirmed Alzheimer's, and she has two copies of the four. She or somebody where you really want to do testing, even though she has no symptoms, right? So and she turned out to have amyloid in her brain and she's being treated to clear the amyloid. So there is, I think, a role for preclinical testing in people who are at high risk, but the vast majority of people we should be careful. And if the blood tests are positive and it's surprising, you may really want to get further testing to confirm the diagnosis because otherwise, as an international working group very eloquently put it, you have a large population of, quote, patients in waiting unholy people waiting to become patients, but maybe in the process changing their whole approach to living. Yeah. Yeah, you got to be careful. Yeah, this is to me what separates this type of screening from cancer screening. Obviously, I'm very vocal about my view on early and aggressive cancer screening. I certainly take a lot of criticism for it, but I find it very easy to defend the position. And I won't do it now. However, I think the type of screening you're describing is fundamentally different, not only because of the pre-test probability, but because of the implications of what to do about it. And so I think your approach makes a lot of sense. And unfortunately, yeah, go ahead. Just to go back to your cancer analogy, when PSA screening first came out, you know, a while back, the incidence of patients being diagnosed with prostate cancer just rose dramatically. And it was only a few years later that we were able to approach it in a more nuanced way and understand that PSA levels rose as we get older. So you really want to plug all the factors in rather than just knee jerk, oh, high PSA equals prostate cancer, you got to figure out age, et cetera. And similarly, I think we will probably arrive at a more nuanced approach to the presence of amyloid and equating that with a diagnosis of Alzheimer's disease. So let's talk about the patient you just mentioned, only in the sense that it's a great foray into maybe something that is not the standard way we would treat. So the example you gave is a highly functional woman in her fifties who carries two copies of the E4 gene. And again, I think just maybe for the sake of ensuring everybody is familiar with what the statistics are. If you're carrying two copies of the Apo E33 gene, so if you're the wild type, you're going to have a particularly noteworthy family history, what is your lifetime incidence as a male and a female for developing Alzheimer's disease? I'm going to let you come up with those numbers. Okay. You're probably going to have a big sign up. No, I mean, I think I think for, you know, it's in the ballpark of gosh, I don't even know anymore. I was going to say it's probably about 6% for a man 10 to 12% for a woman. If you're a three three. But it could be a little less than that. Yeah. Yeah. For me, yeah. The way I think about it is I say, if you have two copies of the four four, that kind of is akin to you having rock at the rock of gene for breast cancer. So it increases your risk by 60% as opposed to the wild type. So, so this woman has two copies of the E4 gene, which again is not deterministic the way the PSEN1, PSEN2 or APP genes that you loosely referred to earlier may be closer to deterministic but again, it is a heavy, heavy risk modifier. And she's totally fine, but she's saying, look, I don't want to wait until I'm not fine. So is there something we can do? And of course, everything is predicated on the belief that the answer to that question is yes. If the answer is no, then why would we do anything about this, right? But the answer is yes. So she comes in, did you go straight to the emeloid brain scan or was that just the first thing that came up positive in the suite of testing that you did? That was the first thing that came up positive in the test. Actually, she was a person where we did a spinal tap. So the level of amyloid in the brain was determined by the presence of low amyloid because most of it is getting deposited so that there's very little in the spinal fluid amyloid. And she also had tau that was kind of borderline. And she had two copies of the floor. And yeah, this is very important actually. People will come to me almost. every day who is a new patient and says, oh, you know, I have a family member with Alzheimer's. And I always asked them, how was that Alzheimer's diagnosed? Was it diagnosed by autopsy? And the answer is almost never. Yes. And up until 2007 or 2008, when we had the spinal tap, we really had no way of diagnosing people anti-mortem before death. So whenever people say they have Alzheimer's, I actually in my family history write down that the person has a family history of dementia, but we don't know what type it is because most often they may not have had Alzheimer's. But in this physician's case, because I also happen to take care of her father, I know that he really did have Alzheimer's because we've done all the tests, the amyloid and the PET scan. And the mother who had died did not have an autopsy, but most likely had Alzheimer's as well based on her presentation. So in her case, even though she did very well, overall, she may have had a couple of areas that I was not quite happy with on the cognitive scores, you know, things that gave me pause. Her language wasn't quite as fluent. Maybe there were a couple of areas where a memory could have been better for a physician compared to her overall ability, which was quite high. And therefore, we opted to start her on a whole slew of preventive treatments to help her reduce weight. She was she went on a GLP one, but she also went on a monoclonal antibody to remove the amyloid that was beginning to build up in her brain. And I think that was something that I was very excited to do with her that she was very excited to embrace because now there was a possibility that we could change her destiny, you know, and that's really the kind of thing I find wonderful. Okay, so let's let's talk about these anti-amyloid therapies because there are a little bit of a mixed bag. In fact, I don't know the order, but was edge-economab the first one that was approved? Yes. Okay. And gosh, it's hard to believe how fast time has flown, but I want to say it's been, was this pre, this is probably about six or seven years ago? So out of count of them, I could tell you exactly when out of count of them, out of count of them, I was approved in July of 2021. Oh, wow. Post COVID. And I just thought it was pre COVID, but it was a very controversial approval in the scheme of things because there was an advisory board to the FDA that recommended against approval. I'll let you explain why. The FDA decided against entirely within the purview of the FDA to go against its advisory board, but it's just not often the case. But in this case, it did and it went ahead and approved the drug. So walk us through the controversy there. Why did the advisory board say one thing in the FDA and other? The advisory board was not, so the adeconomab, which is a drug that clears amyloid plaque in the brain. So it's a monoclonal antibody against amyloid. As are the two other drugs subsequently approved, lecanema, lecanbi, and donanema, kisunla, all these three drugs reduce and eventually eliminate brain levels of tau. So that when you, the person's been on the medication for some time, there's no longer any plaque in the brain. The problem is that it's not necessarily associated with clinical benefit. And that's really the crux of the problem that the advisory board had was that even though the drug was effective in clearing plaque, it was, it didn't necessarily translate into significant clinical benefit for the patient. And it was associated with serious side effects, including brain bleeding and brain swelling. And it was not insignificant in cost. When it was first approved, I think it was somewhere in the mid $50,000 range per year for treatment. So for those reasons, there was a department and I think several members left the ad right. There was a lot of boo ha ha around it, but it was approved. And I actually was one of the first adopters of ad canema because I thought that despite the controversy, I felt that if we could move the needle a little bit for patients with Alzheimer's, it was worth trying. So I started using it and because the drug had a greater than 40% incidence of abnormal brain bleeding and brain swelling as a result of the use of the drug, I developed a very, very slow titration protocol. My reasoning with this protocol was, well, the amyloids been developing over decades in these patients. There's no reason to go in and quickly accelerate the dose saying we could go at it slowly. So what if it takes two years to clear the plaque as opposed to a year and a half? And another big problem with these drugs, as a group, all three drugs, is that they are not generally used for patients who have two copies of the apoi for allele. The feeling being that these patients who have two copies of the for allele are much more likely to have significant aria, which is amyloid-related imaging abnormalities, edema, and hemorrhage in the brain. But the problem is the patients who have two copies of the for like my physician patient are the ones who are most likely to progress and also the ones most likely to need this drug. So I've developed a protocol where we start and titrate patients up very slowly. And in fact, recently for the drug, Donanemab, which is a third drug in this group, they have the FDA has approved a slightly slower titration protocol than initially used because they too have noticed that a slower protocol is helpful in drastically reducing risk of side effects. The one thing I will say is that if you look at the amount of change, what's called the CDR sum of boxes change between patients on drug versus patients on placebo on all these three groups, Lecannemab, which is a second drug, adicannemab is no longer on the market, it was taken off the market. So we're really only talking about Lecannemab, but Donanemab, Lecannemab is a once every two week drug intravenously. Donanemab is a once a month drug. If you look at the changes on the CDR sum of boxes scores, which is changes in memory, ability, et cetera, the changes are small. It's point three or point four points out of 18 points on the CDR sum of boxes score. This is a very small change. And in fact, in the early data on Donanemab, there was really no change on the CDR sum of box scores between patients on drug versus patients not on drug. But I do believe that many of these patients had moderate to severe disease. So if you treat patients early on before there's a lot of tau pathology, before there's too much synaptic loss, then you are able to, I think, have greater benefit. And that's been shown to be the case. And then, of course, there's a question of what if you treat people before they ever get the symptoms? What if they have the amyloid, they're at high risk, like my physician patient, are you even able to prevent the disease? So these are questions that we don't know. But certainly in my patients, even that, you know, what I would say to your listeners is if they have two copies of the four four, they may benefit from a very, very slow titration protocol. And we've published on it. And our data is we find about a 4% risk for amyloid related imaging abnormalities in such patients. Can you tell me what is the sort of boilerplate incidence of ARIA, these abnormalities, these amyloid related imaging abnormalities in four fours to contrast with the 4% you're seeing in your series? So generally, what happens in patients who have two copies of the four four is they have a lot more cerebral amyloid and geography to distinguish it. So amyloid deposited in the blood vessels off the brain. And this amyloid can sometimes cause a break in the continuity of the blood vessels going into the brain and cause small micro-hemorrhages when there's bleeding or can cause white matter changes. It seems as though people who have two copies of the four four have higher prevalence, more severe cerebral amyloid and geography and are more prone to developing ARIA and ARIA H. Amyloid related imaging abnormalities with edema or with hemorrhage and are also more severe. So much more likely to have larger bleeds, more edema and more problematic. This is also one reason people often get confused. They say, "Well, why is it that people on placebo develop microbleeds?" As did people on drug. That's because microbleeds can happen in people who have cerebral amyloid and geography, regardless of anything. So the fact that you get the monocle antibody, it increases your risk, but you may have a baseline burst anyway because it's not. you have two copies of the flu or even a copy. Okay, so let's go back to the very beginning on that. So, adicentimab is approved. The controversy is basically, it improves the biomarker. It doesn't improve the disease. The example I would give here is it's a drug that lowers LDL cholesterol but doesn't prevent heart attacks. You decided, and I don't want to sort of paraphrase or misrepresent, but I think what I've heard is, look, you said, there's an alternative explanation here. A, we could be looking at two short a period of time, B, we could be looking too late in the history of the disease. If we intervene earlier, give ourselves more time and mitigate the side effects by ramping the drug up slower, we are after all removing amyloid and amyloid is playing a role in the disease. Is that a fair assessment of the nuance that you sort of applied to the first drug, which is no longer there, but the logic still applies to the second and third? That's correct, yeah. That's exactly right. The other thing, Peter, I always ask myself, anytime a new drug comes out, is, would I want this drug? If I had Alzheimer's now, knowing everything I know about this drug, would I want to be on this drug? I felt that without a can of my answer was yes. That's why I started giving it to my patients. Was it ultimately pulled off the market because of area or was it pulled off the market because of lack of efficacy? It was pulled off of the market because they required post monitoring of the drug because of the controversy and that became financially for the company, I think, unfeasible. Got it. What is the annual cost of Lecana Mab and DeCanama? They cost, the drugs themselves cost about $26,000, but then there's the administration fees, which can range sometimes in institutional settings, they can be as high as $10,000, just they'd fuse the drug versus you go into an infusion center and it could be $400. There's always that spread per infusion. Then there was a cost associated with the MRIs that the patients might need, which they need, and then they need amyloid imaging. One of the things that I unfortunately have discovered is the insurance companies, especially with Lecana Mab, which starts at 10 milligram dosing right away, 10 milligram per kilogram. They will not reimburse patients if we start them at a lower dose and titrate them up. In other words, your efforts to protect the patients from area related imaging have normalities is something the insurance companies are saying, "Hey, we don't have a protocol for this. The patient's going to have to pay out a pocket if they want to say for protocol." That's correct. We haven't run into that with the Donat-Mab so much because Donat-Mab does have a 350 to 700 to 1050 to 1400 milligram titration schedule. We've been able to keep people at the 350 for four or five infusions without anybody noticing. But unfortunately, we haven't been able to do that with Lecana Mab because it just starts at 10 milligram per kilogram. We've had patients, Peter, who are four or four patients, who have had severe area on just three milligrams of Lecana Mab, three milligrams per kilogram, as opposed to the 10. Can you imagine what their side effects would be on 10 milligrams per kilogram? The reason for this is simply the higher initial risk. In other words, it's that the Apo, if you're a 3-4 and then ultimately a 4-4, with each of those steps, you're moving towards a higher susceptibility for the edema and/or the hemorrhage in response to the drug. Can you say a little bit more about what it is the drug? I know you've kind of alluded to this already, but what is it that the drug is doing in the process of clearing amyloid or tau that is resulting in edema and hemorrhage? So the antimonicone antibody, whichever one it is, the drug goes into the brain and it starts to clear amyloid in the substrate of the brain, but it also removes amyloid from the tunicum media or the middle code of the small arteries in the brain. That's where amyloid is. So what that does then is it disrupts the lining of the arteries and it causes leakage of initially fluid and that's called edema, ARIAE. And then eventually there's extravization of actual blood because there's a rupture of the lining, there's a tear in the lining of the blood vessels, if you will. And that then causes ARIAE or hemorrhage. And if it's a large enough disruption, then you can actually have a massive brain bleed and there are cases of depth in such patients, particularly if they are on a blood thinner. We have patients who could be on a blood thinner for atrial fibrillation or something like that. Alternatively, also, for example, one of my younger patients who's on it for prevention, she's 51 or 2 and she's developed significant ARIAE on both sides of her brain, on pre-milligrams per kilogram of lachanemap. And she's been on those dill's now for six dill's, which is almost, you know, it's three months. And she still has ARIAE in different areas because her brain is, you know, there's little tears in the fabric of the blood vessels as the monoclonal antibody removes amyloid from the lining of the blood vessels. Now, is she having any symptoms or is this something you're only able to know because you're doing the, you know, concomitant MRIs along the way to monitor progression? Is this something you never want to wait until it shows up symptomatically? You want to know that it's there radiographically and pull back in response to that? That's a great question and the answer is absolutely. So we have a very, you know, rigorous monitoring protocol with imaging. And I will say, I've been using monoclonal antibodies since 2021. So it's been over five years. And I would say I cannot remember perhaps in one four, four patient who was in our early 60s with Alzheimer's, she had some visual findings. But everybody else, we only discovered the brain bleeding and the brain swelling on MRI. Sorry, you're saying that in the five years of your very liberal use of monoclonal antibodies, your incidence of ARIA is 4%, but symptomatic ARIA has only been one case. Symptomatic ARIA has been one case. I did have one case, which was a, and all the patients have stayed on the monoclonal antibody, including one patient who had significant ARIA where he had ARIA is defined in multiple places, some of them rather large ARIA and he had absolutely no symptoms. And this was one of, he was on adacanemab. He was a four, four patient. He was in his early 60s and he had been on adacanemab slow titration and he had gone up to eight milligrams per kilogram. And at month 19 or 18, he developed on MRI significant ARIA, we're talking fairly significant with some micro-hamridges without any symptoms, including on a careful neurologic exam. And how far do you pull back the drug when you see that? So that patient was actually quite scary. I mean, that was my first real, I mean, that was maybe 2024. So before the other drugs had really come out and early 2024. And he, what we did was we realized that the ARIA had happened a few weeks before because of the characteristics on the MRI, it wasn't acute. And he actually happened to want to go to Europe the following week. His exam was normal. So he went to Europe and then he came back and we, I think we cut down to a lower dose. We went down to six milligrams and then went back up again. So it was a scary moment. What I do do now, what I've learned to do is when you have patients who have people with CAA, cerebral amyloin and geography, can have ARIA without, as I said, without any impetus. They can just have spontaneous ARIA, ARIA and E. And generally the way you treat it is you treat it with steroids. So what I do in my patients, who have, who have, like for example, this young woman who's got four four and three lacanemab, three milligrams of lacanemab, who has ARIA, which seems fairly refractory. I treat her with steroids as you would somebody who has cerebral amyloid angiopathy with the inflammation. And we just pre-medicate with steroids and that seems to control it. Pre-medicate. So in other words, you're saying you pro-phylactically manage with a small dose of a steroid before each subsequent dose once you've made the diagnosis of ARIA. So are there any clinical trials that are going on to take this protocol of yours and do it in a randomized fashion because obviously you're doing it in what we would call open label, meaning everybody is being treated this way. Nobody's getting either a placebo or a standard approach. To me, an elegant trial, quite frankly, although I think it would be cost prohibitive, and that's probably why it's not going to be done, would be taking your low and slow approach, what I would call the low, slow early approach. Right? - Yeah. So we take these high-risk patients that are in their 50s or 60s, who are probably 10 years away from clinical disease or five years away from the first symptom, we treat them in a way that is very low, very slow, very safe, and we ask the question, are we bending the course of their disease? Because to me, that's the interesting question. Right? I think what these drugs have demonstrated is, if you take a person who is in florid dementia and you slam them with these monoclonal antibodies, you are not bending the arc of their life. And in fact, if they are E44, you are introducing a staggering amount of risk. In fact, I assume many neurologists would not even treat an E44 late enough in the game with a high enough dose because the risk and reward isn't there. So it's a shame that the companies that make these drugs wouldn't subsidize the cost in a way that would allow a more longitudinal study in what I think is the appropriate patient population. But I'm not going to diminish the cost of monoclonal antibodies. They're certainly more expensive than your typical small molecule, but they're probably not the sticker price. And I think there's more people to be helped if we could do the right study and again, kind of replicate what I think you're doing clinically. Because again, the approach makes sense. If you think about most chronic diseases, time and area under the curve is the issue. Right? We know this with atherosclerosis. If I take a person for primary prevention, I'm not going to move the needle treating them for a year. It's just not enough. I have to treat them for years to move the needle. So anyway, I think that's hard to imagine. So tell me what's on the horizon as far as the monoclonal antibodies? Like where do you see, with every drug, whether it be GLP ones or statins or any drug, they always get better with subsequent generations. So where do you see them going next? I think we're going to have drugs that are more clones that are able to like ameliorate this risk of edema and hemorrhage drugs that can be taken as pills, drugs that can be given at home. And I do want to say the most exciting thing that happened to me, I have a woman in her 70s who came to me with, you should see a television show in which we were discussing Alzheimer's. And so she came to the office. And she turned out to have Alzheimer's. As she's very, very, very functional. Not particularly, I mean, I think her overall ability was at the 70th percentile. So now, one of these Uber-high-achieving people, and we started her on medication after a spinal tap showed evidence of amyloid and tau. And she was on the canemab. She eventually cleared the amyloid. I decided to do a tau scan. She no longer had tau. And you know, there is downstream reduction in tau in all these different, with all these monoclonal antibodies, because even though they target amyloid, they also clear some tau. But she actually had no tau on her tau scan. So now we're waiting on her spinal tap, because I refuse to believe that we've basically erased, removed her pathology. Clinically, she's done remarkably well. So that, again, speaking to the spectrum of Alzheimer's, there are some patients who respond dramatically. And who knows? Maybe her immune system is just different from someone else. I have a pair of identical twins, and I take care of one of the two. And the one she just, you know, she was on a monoclonal antibody, initially on an adicana map and then on donatamaab. And she did much better than her identical twin, who was in a facility. And my patient actually also had heart disease. She had rheumatological heart disease, which destroyed her valve. And she had an artificial heart. And she was on cumidand. And we still decided to put her on a monoclonal and watch her like a hawk. She never developed side effects. And she cleared her amyloid. So I'm just saying that I think it's an exciting time. I really do. And I think early diagnosis really does make a difference now in terms of changing the trajectory of someone's cognitive health. So you've been in practice for 25, 26 years. And these drugs have only been available for five years. So prior to the approval of the first monoclonal antibody, what were you doing for this type of a patient? And what were you doing for the later stage patients? And how much of those things are you still doing today? So I've always, you know, I actually trained in the era of HIV and AIDS. So I, and you know, we all my early patients who died, died from HIV. You'd see them one day. They were dead the next week. And I, for the first time a few weeks ago, saw a patient who actually had not just HIV, wasn't just HIV positive, but actually had clinical, had had clinical AIDS with PCP and Capulsi Sarcola, who had survived going on immunotherapy and IVIG and all of this. And now is in his 70s and concerned about his memory. So I mean, it was the first time that I'd ever encountered that. And the way I've approached Alzheimer's disease is the same way. We don't have a cure yet, but we can give each person a cocktail of medications just like they do with patients with HIV. And in this particular patient, he was on IVIG, you know, so God knows what it did to his immune system. And therefore you can keep the person alive. So and functional, not just alive, but actually functional. And that's important. Yeah. So before the advent of these medical antibodies and to this day, I still have patients on a combination of a colonestrious inhibitor, such as donapazole, galantamine, et cetera, mementine, which is a NMD receptor antagonist, that basically I just say reduces signal to noise ratio in terms of brain neurotransmission. And it also may prevent apoptosis or cell deaths in patients. Depending on the patient, we may have them on something like Balocyclovere, some patients benefit from other immune modifying treatments when needed and better control of their cool morbidities. Many patients have may benefit from interventions like ventricle peritoneal shunt for hydrocephalus. And the other area that I feel is important is maintaining a person's neuronal connectivity. And by that, I mean, how well the networks function. And for that in 2008, I started using transgranular magnetic stimulation, targeted TMS, to help maintain function. And TMS works by stimulating the brain using magnetic stimulation that then creates a small area of current just under the area of the coil. So an area about 1 centimeter squared of the cortex gets stimulated. And then that creates stimulation in the circuitry to which that area of the cortex is attached and the whole connected. And the hope is that by that method, you're able to keep those circuits alive regardless of the pathology. Regardless of whether the pathology and the cognitive impairment is from stroke, from menopause, from Alzheimer's. And over time, we've kind of refined this process. And so I continue to use TMS in patients. And I find it particularly helps people with language problems, for example. Are you using TMS with EEG guidance? I know that that's something that's becoming a little more popular with psychiatric disorders, such as recalcitrant depression and things of that nature, but not sure about your application. I've really always used TMS using neuron navigation guidance of anatomical structures. So we actually have kind of a-- we plug in the patients MRI, and we kind of create a GPS of that person's brain. And then we mark those areas that we think need to be stimulated. And I usually stimulate the dorsal lateral prefrontal cortex, roca's area, the pre-cunius for parietal and visual spatial skills. And some patients, we also stimulate the auditory-- the wernichis area. And again, this is off label, because TMS is only approved in the United States for treating depression and for certain electro-diagnostic purposes. But we've been using it off label since 2008 for treating our patients with dementia. How optimistic are you on the causal nature of the relationship between GLP1 agonist use dementia? Obviously, the observational data appear favorable. The challenge with data of this nature is it's a little difficult to establish You have obviously the healthy user bias of people who can afford and use and comply with these drugs. But of course, you have the bigger issue, which is any drug that is resulting in weight loss and an improvement in metabolic health is going to improve risk. And that might alone be a reason to use it. But the real question is, do these drugs offer a benefit in risk reduction through an inflammatory pathway or a pathway that is not so directly tied to weight loss of insulin resistance? I believe so. I think the GLP ones offer an advantage and even the older drugs like metformin may offer benefit in this area. And so I do use it in my patients where I think it's necessary. And the other thing too is obesity is finally coming down in the United States. And I'm going to ask the GLP ones and I'd be very curious to see what happens as a result of that with so many diseases associated with the brain, many of which are driven by obesity and cardiovascular disease, which is a direct consequence of diabetes. We've talked a lot about Alzheimer's disease. I do want to just give a little bit of time to discuss vascular dementia and Lewy body dementia. And I'm assuming you see quite a bit of those in your practice as well. Can you walk us through a how those diseases present and be how you diagnose them? It's very rare. Alzheimer's almost never presents in isolation. So they've done autopsy studies in patients and find that between 98 to 99 percent of patients with Alzheimer's have some kind of concomitant primary brain pathology. And the most common is vascular disease, vascular brain disease. But in terms of the primary vascular dementia, I find that rare than you might think because so many of us as we get older will have some vascular disease in our brain. You know what I call white matter schmutz in the brain and used to be taught off as rather benign. Now we know that it is not benign that it interrupts the connect home of the brain and it's progressive and causes problems that perhaps interfere with the resilience of the brain to pathology and therefore needs to be addressed specifically. So I'm fairly rigorous about treating patients with vascular dementia often with concomitant other conditions as well. And one of the things that I do do in my patients who say have multiple strokes in their brain that I believe are the primary cause of their cognitive impairment is, you know, aside from putting them on statins and all of that is if they do have atrial fibrillation or some kind of a heart problem that is the cause of the strokes, I recommend a watchman so that they can then go off the anti-cragling medication, eloquist, Xeralto, etc. Because many of these patients are at higher risk for faults just from their vascular pathology, they have dementia so it just prevents an added problem down the road. Along those lines in patients who are on blood thinners or atrial fibrillation or another condition would then have Alzheimer's disease and therefore are precluded from going on a monoclonal antibody because of the blood thinner, I recommend them getting a procedure like a watchman so then they can go off the anti-cragling and then get on the monoclonal. So I've done that with a few patients. Louie body disease, you know, if you look at patients with Alzheimer's, about 40% of them eventually will have some level of Louie body pathology. If you look at patients with Louie body, about 30 to 40% of them have Alzheimer's pathology and some people think even a higher number. So the two conditions co-exist quite a bit. What I find the most troubling in my practice is the number of patients with Louie body who get diagnosed as having Parkinson's and therefore are treated with Parkinson's and medications, levodopa and parbedopa, the dopamine agonis like meripax etc. And that actually worsens their Louie body. They get more confused. It doesn't really help with their symptoms and I have quite a few of those patients. But in terms of a diagnosis, for me, again, it's not as straightforward as you might think it is. I do almost in all my patients in Louie body, I do work them up also for Alzheimer's because of the vast cool morbidity overlap between the two and if they don't have any of the Alzheimer's biomarkers and they have only a Louie body biomarkers which is primarily we do dopamine scans. We can also do skin biopsies to see if they have alpha-signor clintopology. Can also do a spinal tap, send the fluid off for alpha-signor clian. You make the diagnosis. The one thing I will tell people is there is, I think, a fairly prevalent misconception that Louie body disease is rapidly progressive and causes death in five to six years. And I'm here to say that that is absolutely not true. Patients with Louie body in fact respond fairly well to treatment and sometimes better than patients with Alzheimer's. Some patients actually get dramatically better. And as far as I'm concerned in my practice, the life expectancy is not that different from patients with Alzheimer's. Can we talk a little bit more about the pathology? So how much is Louie body dementia impacted by APOE4, first of all? Everything is important impacted by APOE4, unfortunately. And I think it has to do so much of what happens in the brain has to do with robust clearance of pathogen. And whenever you have E4 pathology, it interferes with that. So I think there is a slight increase. I mean, obviously it's not as dramatic as for Alzheimer's pathology, but does increase risk. So tell me or tell us the role of alpha-synucleon in the pathology progression. Is it a target of therapy? Does it play a role similar to amyloid? Obviously, I mean, maybe start with the easiest case, which might not be that realized, but a pure case of Louie body dementia without a significant overlap of Alzheimer's disease. So what's happening? What's the order of events in pathology? So the problem is that Louie body disease and Parkinson's disease share the same pathology, which is abnormality in the alpha-synucleon protein. And the difference is, sadly, a difference of time. So if you have motor symptoms for less than a year, during which time you then develop cognitive symptoms, then it's Louie body disease. Whereas if you have motor symptoms and then after a period of time of over a year, and some people say two years, then you have Louie body disease. It's kind of an arbitrary distinction. In addition, with Parkinson's disease, the pathology that it's alpha-synucleon pathology is primarily confined to the area of the basal ganglia, whereas in Louie body disease, it's more widespread. And any disease will eventually, and then Parkinson's, what, how do you differentiate Parkinson's disease related dementia, which is, so people now, I think, more and more people are, again, going back to the spectrum concept, think of the alpha-synucleon spectrum disorders, of which Louie body and Parkinson's disease, all of them are on that same spectrum, and the presentation may be different. One way I distinguish between Parkinson's Louie body, because sometimes it's very hard to tell exactly when somebody begins to have cognitive changes as we've discussed the smarter the person, the easier it is for them to compensate, is to look for a rest tremor. I have, in fact, never seen a patient with Louie body present with initially with a rest tremor. So that classic pill rolling tremor of Parkinson's disease, I've never seen in a Louie body patient ever, and we're talking. So does that mean that by definition, Louie body, while the alpha-synucleon is diffuse, it's sparing the basal ganglia. No, because in Louie body disease, by definition, you've got to have motor symptoms. So why do you think they don't pill roll? That I don't know, Peter, this is one of the mysteries of neurology that I haven't figured out yet. But that's what I've noticed in my, and that's what I use to make my distinction. Obviously, when you do a DAT scan, there are classic patterns that you see in Louie body that you don't see in Parkinson's disease. But again, that is not quite as rigorous and as distinctive as you'd like. But it's important from a clinical perspective, because if you have Parkinson's disease, you would want to treat with drugs that increase brain levels of dopamine, whereas if you have Louis body disease. Adding dopamine can cause serious negative side effects, including psychosis, worsening the psychosis and patients with Lewy body. So Lewy body disease clinically is diagnosed by the presence of motor disorder, Parkinsonian features, fluctuating consciousness, cognitive impairment, and often visual hallucinations. And these can be quite dramatic. And the one thing also about the visual hallucinations of Lewy body disease is patients have insight into them. So for example, I was talking to the mother of a physician who is my patient who has Lewy body disease and she's a wonderful woman. She's in Florida now and I was talking to her on the phone and she said, "Yeah, you know, I don't understand. I was very, very clear that I was not in my house and everyone else told me I was in my house." And I kind of knew I should feel like I was in my house, but I really didn't think I was in my house. Now Alzheimer's patients rarely ever say that. They don't have that insight, usually. Patients with Alzheimer's can also have those kinds of hallucinations and delusions, but their insight is not as crisp or else I'll have a patient say, "You know, I call the cops because I saw these people on the street and I knew because I've done that, I've done this before that they were not real, but they absolutely looked real to me." And even though my wife told me not to call the cops, I called them. I mean, that has to be beyond terrifying. I mean, that's almost like even though it's a completely different disease. I mean, that almost feels like schizophrenia minus the voices. Yeah. Yeah. Yeah, it's rare to have auditory hallucinations. In fact, I've never had a patient with that in my practice. So what are the differences? Once you have the diagnosis made, what are the differences in your playbook of treatment? And are you catching these Lewybody patients later in the disease? Do you have fewer tools to identify early alpha-synucleon relative to emaloid beta? We have fewer widespread tools, right? So we don't, I mean, skin biopsies now are great, easy to do. You can't. And I'm pardon my ignorance. That is news to me. I didn't realize you were biopsying the skin for alpha-synucleon. I thought you were getting it out of CSF. So why does this same protein that is involved in neuronal geography, making its way into this skin? And how do you link what you're seeing in the skin to what's happening in the brain? So they travel along the neural pathways, so because your skin is full of neural nerves. So you're really, when you're doing a skin biopsy, you're really not. You're doing a nerve biopsy. You're doing a nerve biopsy, but you're doing a biopsy of the small, cutaneous nerves in your skin. Wow. So you do punch biopsies on your neck, further down in your knee, and then further down, so you kind of see how much sinew claim there is at each level. And the more sinew claim you see further from the nervous system, the more likely it is to be widespread disease. But, you know, there are so many conditions that can mimic motor disorders that are not caused by sinew claim. So what this skin biopsy is do is that they distinguish between them. But that's only giving you information above sensory nerves, correct? Yes. It gives you information about, yeah. So that's, you know, relatively speaking in the grand scheme of the cortex, that's relatively small real estate. So the other stuff you're doing clinically, so you'll, you would infer based on visual hallucinations that the occipital lobe is involved in things like that. Right. No. So we, so for dementia with Louis bodies, again, as I say, I work patients up, even if they have Louis body dementia, I always work them up for Alzheimer's because I know that there's such a cool morbidity between them too. But the thing that I often will do is I will do a DAT scan. So when you have a dopamine uptake scan, you can tell if there is abnormalities in the basal ganglia that would be consistent with alpha, could be consistent with Louis body disease. But then you can't really be absolutely sure until you do the biopsy to verify that it's alpha sinew claim that's driving the pathology. In terms of treatment, one of the most important things that I do is get them off their Parkinson's medication. And that can be very difficult because patients, I found a lot of the high of the Parkinson's medication. I saw a patient yesterday, actually, a new patient who was in her 70s had been having of what's called an essential tremor, which is a fine tremor that many of us have, but that can also be present. There's a cool morbidity between essential tremor and the tremor of Parkinson's disease, but she never had a rest tremor. She had, despite a negative DAT scan, she had been put on levedopa, carbidopa, three tablets, three times a day of 25100, add an academic institution for treating Prozimal Parkinson's disease, despite her negative DAT scan. And the thing she told me is, you know, she says, listen, these pills really help me because right before I'm ready to take the next set of pills, I start to feel a little bit down. So you have an internal kind of low and the pills kind of reset you because of the dopamine high. So patients are often averse to going off the pills. So one of my tasks with her, because she's been on these nine pills a day for the last year, is trying to get her off those pills. And she really didn't have the tremor that she had was in this central tremor and not the tremor of Parkinson's. So what are the predisposing factors for Lewy body dementia, where it's the dominant form of dementia. So yes, there may be some overlapping vascular and/or Alzheimer's dementia. But I assume family history poses a risk. What are some other known risks for Lewy? So family history, family history poses a risk, but the problem is, I mean, let's assume it's diagnosed correctly. I know that that's a, that's its own problem with diagnosis. Right. The problem is that with, yeah, if it's, if it's diagnosed correctly, what are the risk factors? I mean, Lewy body usually occurs in patients a little bit younger. Again, vast risk factors increase risk for Lewy body disease, Alzheimer's disease increases risk for Lewy body disease, Parkinson's disease increases risk for Lewy body disease. And actually, it's an actual tremors also will increase risk because they are on that spectrum of possibly kind of morphing into. But do we think that those things are increasing risk or their presence is a demonstration of other factors that are underlying the risk? In other words, whatever it is that's causing everything you just said happens to increase the risk of Lewy body, but what are those other things? In other words, does metabolic dysfunction, just as we believe metabolic dysfunction is truly causally related to the risk of Alzheimer's disease, do we think it is, and by the way, the important point there is therefore it is treatable, right? Therefore we target aggressively hypertension, dyslipidemia and insulin resistance because those three things we have such conviction are causally driving Alzheimer's disease. Do we have the same level of conviction around Lewy body dementia? I feel anything that's good for the heart is absolutely good for the brain regardless of the pathology in the brain. And having said that, I feel like we don't yet have enough knowledge about Lewy body disease because we just we don't have that. We don't have the data yet. We don't have a robust enough data. Yeah. Yeah. By the way, female male difference in Lewy body, is it one to one, two to one? How does it compare to Alzheimer's? I think there's again a slight, there's more, there's more men with Lewy body disease, but that's also because we've got more men with Parkinson's and we might be capturing, yeah, we might be missing incorrectly. Got it. Let's go back to females with menopause. Who coined a term I'm blanking on it like mercy menopause related cognitive impairment? Is that, did I get that right? You did. I'm very impressed. How did you remember that? I have a great team of analysts that remind me of these things. So is it say, I mean, is there ever an indication where, is there ever a scenario where you, you have a woman who's come to you, she's got a history of breast cancer and you're, you're just saying it's not worth the risk or she's, she's too afraid of the risk. We may or may not be familiar with my views on the relationship between estrogen and breast cancer, but, but let's just say let's take an extreme case, right, which is she is actively undergoing treatment for breast cancer in which case if it's estrogen sensitive, you clearly wouldn't give her estrogen. But outside of an extreme situation like that, do you consider estrogen and then by extension progesterone if needed to oppose it sort of mainstays of maintenance therapy for women in either prevention or even the treatment of disease? Yeah, I mean, I think those, those, you know, in patients who are not where there's no contra indication, we do give recommend estrogen. And now there's thing that really work speeder for women like this, for menopause related cognitive impairment, is just targeted brain exercises. You know, the brain is fantastic at the concept of learned non-use, so that you could have a stroke and suddenly not be able to move your right hand. And this could go on for 10 years, but let's say I restrict my right hand, I put it in a sling, I'm sorry, I restrict my left hand, I put it in a string, and all of a sudden I don't have my healthy left hand to help, all of a sudden 10 years later, your right hand starts to move, that's the whole concept behind constrained, induced movement therapy for stroke. And I find that the same can happen in menopausal women. So the same problem happens in menopausal women, where if they start to have trouble with coming up with words, the very common problem, or they're having trouble multitasking, they just stop doing it as they, there is some disuse, dysfunction. And so when you actually force them to use those areas, when you do targeted brain exercises, even just as little less once a week, forcing them to use those areas, they recover function quite dramatically. You can also in such women use drugs like colonestrace inhibitors, because the underlying mechanism of cognitive impairment is ultimately loss of acylcholine in the nucleus-based salus and areas of the brain in these perimenopausal women. And so those drugs can work. We actually years and years ago did a double-blind placebo-controlled trial of Donapizel versus placebo in women going through a menopausal with cognitive impairment and found a trend in 21 patients, 21 on drug, 21 on placebo, for improvement in cognitive function in the Donapizel group. So I think those are then brain stimulation, transprimal magnetic stimulation, seems to help women in this situation as well. So there are multiple different ways that we can help. On the other side of the coin, I have patients who are on an antestrogen for treating breast cancer, or ovarian cancer, an astrosol, an astrosol, to moxavinet, et cetera, who are coming in with severe cognitive impairment because of that, who actually want to go off of the drug, regardless of personal risk, because they just can't stand how their brain's functioning. - Yeah, I think this is one of the real pleasures of being a clinician is your patients teach you a bunch of stories. And I think back to one of the first women that taught me that lesson in 2014 or 2015. This was a woman who also came to see me, status post, mastectomies, bufurectomies, hysterectomy for, I think, primary breast cancer, but bad genetics. Anyway, she was taken off all of her hormone replacement therapy and the course of chemotherapy in her life turned out to be devastating. So she was really far down that spectrum of mercy in the sense that basically functionally debilitated. And she was a young woman, right? She was in her 50s. So went from being completely normal to, you know, couch ridden effectively, due to brain fog and just inability to do anything. And she came to me with the suspicion that I think this is due to the loss of hormones. I think this is due to the hormone withdrawal. And, you know, after many, many discussions, not only with her, but with some other physicians, we decided to take the risk and take her and put her back on her hormones. And the recovery was remarkable. I mean, it wasn't subtle, right? So it was very quick that she regained her cognitive faculties. And so with a takeaway for me was both the physiology, but also the choice, which is for some people, and I would probably put myself in that situation, I'd rather deal with the risk of cancer than cognitive decline. Yeah. But again, it's the bigger question is, it should be a choice. And I also have a little bit of an issue with how aggressively aromatase inhibitors are used for things like DCIS, which I think is, I don't think patients fully understand just how small the risk is that they're mitigating with an aromatase inhibitor for five years in the context of a precancerous lesion. And so I think there are these edge cases where we're doing a lot of harm without a very clear benefit. I can't agree more. And I totally, I can't tell you, I mean, patients that I've worked with were also being seen by folks at Sloan Catering, for example, in New York, and have decided with me to your point about choice that they would rather risk the possibility of recurring cancer than risk the ongoing ineptitude and inability to function in their lives. And again, I saw a young girl, this can happen, the lack of estrogen driving brain fog, a 21-year-old girl that I see for migraines, who's in college, and she spoke to me earlier this week, and she said, for the last six months, she's been a complete fog, complete brain fog. She can't function. She's in a good university. And I had her go see her gynecologist, she hadn't had her period. And so the estrogen level for her came back at 22, pycograms per desi, it's very low. As you know, menopausal women, it's less than 30 or 35. So hers was extra ordinarily low, and we don't really know why that is. - And was her FSH or LH elevated as significant? - They were not. So it was very interesting. Her FSH and LH were normal, but it was almost like primary ovarian failure of some sort. But in the meantime, she's not able to function. She cannot work at school. And this is not some, and so I told her I said she may benefit from some kind of low-dose oral contraceptive while they're trying to figure out what they should do because she needs to be able to finish school. - And in the cases where you're managing the hormone, do you prefer a transdermal estrogen to an oral one given the other changes with the increase in SHBG and binding capacity and things like that? - Yeah, I mean, I actually prefer transdermal, you know, either a gel or a patch, because yeah, you have lower risk in my, in my, for me, the big considerations, lower risk of strokes and venous clots. - So you've been on this really incredible journey. You're at the forefront of what can only be described as a very, very personalized nuanced approach to the early treatment of dementia's, across the board. What do you believe today that you absolutely flat out didn't believe 10 years ago? Like what have you actually changed your mind on? - I never thought that patients with Alzheimer's could get better. - And you really, you really believe that that is the case. - Oh, 100% of the difference. - Because that is just not conventional wisdom, right? - Yeah, no, I never, never thought. And even before, even before we had the more clonels, I had patients who got better with treatment, which just didn't make sense. And I used to think before we had the biomarkers, before we had the spinal taps in 2007, I used to think maybe I made a misdiagnosis. Maybe this person didn't really have Alzheimer's, because, you know, the teaching is that every person with Alzheimer's inextrabley declines. And we also know that 30% of patients in drug trials were with the drug trials for Alzheimer's didn't actually have Alzheimer's by mythology, right? They were misdiagnosed, clinically. So I used to think that, and then I realized when I had the biomarker ability that actually patients with Alzheimer's could get better. And that was, it took me, I think I've been in the field specializing in this area since 1994, Peter. And I think for the first six, seven years, I was just learning about it. And then I started seeing patients would get better with treatment. Sometimes something as simple as just brain exercises, which didn't make sense. And I always thought we misdiagnosed them. And then when 2007 came along and we had the actual ability to diagnose pre-antimortum, I realized that patients could get better. Then it took me another five, eight years before I truly believed it, truly believed it, because it's so ingrained, was so ingrained that that was not even a possibility. And now I really do believe it. - When you think about the next 10 years of your career, what do you think is going to have the biggest impact on your ability to reverse Alzheimer's disease or prevent Alzheimer's disease? I think for preventing Alzheimer's disease, what's going to have the biggest impact is AI for early detection. of changes in our patterns of thinking. In addition to a cocktail of medications designed to emellurate first inflammation and then pathology and high risk group patients. And in terms of treatment, I actually think targeted neuromodulation will be important in addition to drugs to reduce pathology. Do you know if there are any drugs specifically in the pipeline for neuroinflammation? Obviously, the field of immune modulators is a popular field, though it's often around autoimmune diseases and oncology. But do you know if there are people specifically targeting neuronal inflammation? I mean, there are. I actually can't. I know there are, but I can't think of anything right now. But there are drugs in pipeline. Yeah, yeah. And I will tell you, years ago, Norm Rehlkins' group at Cornell had the IVIG, which is pooled autoimmunity, infused into patients who had Alzheimer's disease. And I actually used IVIG in a whole group of my patients with Alzheimer's diagnosed by spinal tap analysis. And two of my patients became plaque negative. And one of them stayed stable for 17 years, and the other one is still stable. So they eventually, the feeling was that IVIG had no place in treating Alzheimer's disease. But if you looked at the analysis, people who had the APOE for allele, are far more likely to benefit from the drug than people who did it. So that was an early. Which is really not surprising. I mean, we see this over and over again. I know you and I have spoken about Obesetropib and the profound impact it's having, at least in a pilot study when you look at the biomarkers. But the impact is most profound, the more severe your risk is. So the IV IVs actually have reversal. IVs have a dramatic blunting. So again, I think what I hope comes out of this, and where I hope the world is in five years, I don't even want to wait for 10 years, is I hope that more people are taking an approach like you are through clinical trials, where we're doing better identification and stratification of risk and tailoring treatments. Because as you said, the biggest risk of the current landscape of these treatments is that we are trying to take a very, very, very heterogeneous group of genetic predispositions, other comorbidities, disease manifestations, and we treat them with one hammer. We hit everybody with the exact same hammer and we blunt all of the potential responses. Now, I think that's true, unfortunately, in most clinical trials for most diseases. It's true in the way we manage diabetes and heart disease and cancers, although with cancer, at least you now see gene targeting and mutation drivers and things like that. So my hope is that that's where the field goes and that we start saying, we're not treating Alzheimer's disease. We're treating this subtype of Alzheimer's disease in this subset of patient. Just as we don't treat breast cancer, are you triple negative? Are you ER positive? Are you her two new positive or negative? Are you completely different diseases for all intents and purposes? So I think the work you're doing is important because I think it's helping people start to hopefully align towards that path of both diagnosis and treatment. Yeah, I think you're 100% right. There is no more heterogeneous disease I can think of. No more than Alzheimer's disease because it's each person with Alzheimer's disease because they're own private version of Alzheimer's disease. That is different from everyone else who has the disease because that person has their own individual brain. So that, you know, what's really startling, you know, is you take two patients identical twins with Alzheimer's and you find their studies, publications, that the risk for Alzheimer's is dramatically different in identical twins who are raised in the same environment. Sometimes one of a pair of twins doesn't get the illness for 10 to 15 years after the other one. How does that happen? Because their brains, although as identical as they are, are still different and that is really what drives the illness as well as inflammation, epigenetics, so many things and you absolutely needed nuanced approach. Well, Dr. Debbie, this has been a fantastic discussion and I learned a lot, but more importantly, I think everybody listening did as well. So thanks for taking time away from your clinic to join us and I'll look forward to many more discussions with you on these topics. Thank you very much for having me, Peter. That was great. Thank you for listening to this week's episode of The Drive. Head over to peteratia-md.com/shownotes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter all with the handle Peteratia-md. You can also leave us a review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional healthcare services including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. 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