#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.
00:01:42.560and lifestyle interventions. I've wanted to have Dr. Debbie on the podcast for a while now
00:01:47.260because the field of dementia is changing rapidly. For a long time, Alzheimer's disease
00:01:51.920was viewed as really kind of a one-way decline, diagnosis with very little room for nuanced
00:01:57.320intervention. But she takes a very different approach, one that is highly individualized,
00:02:02.060focused on early detection, careful risk stratification, and matching the right
00:02:05.660combination of treatments to the right patient. In this episode, we talk about how to think
00:02:10.920about dementia as a spectrum, including Alzheimer's disease, but also vascular dementia,
00:02:15.420Lewy body dementia, and many other mixed presentations in between, as opposed to discrete
00:02:20.540diseases. The evolving biology of Alzheimer's disease, including amyloid, tau, neuroinflammation,
00:02:27.040and why pathology does not always map neatly onto symptoms. How she evaluates high-functioning
00:02:33.320patients with very subtle cognitive changes, and how she thinks about biomarkers,
00:02:38.020APOE4 risks specifically, and testing asymptomatic people. We talk about anti-amyloid therapies,
00:02:44.440which have become very controversial, although slightly less so today than when they were
00:02:48.780initially released, including lacanumab and decanumab, their risks and benefits and her
00:02:54.980approach to reducing side effects, including the most devastating side effects which we talk about,
00:03:00.520why some patients with Alzheimer's disease may stabilize or even improve with a personalized
00:03:05.160multimodal treatment strategy, the overlap between Alzheimer's disease, vascular dementia,
00:03:11.320and Lewy body dementia, including why Lewy body disease is often confused with Parkinson's
00:03:16.360disease, the relationship between menopause, estrogen, and cognition, including her specific
00:03:23.300concept of menopause-related cognitive impairment, and finally, how early detection, AI-assisted
00:03:30.080monitoring, neuroinflammation, targeted therapies, and more personalized treatment may reshape the
00:03:35.980future of our dementia care. So without further delay, please enjoy my conversation with Dr. Debbie.
00:03:49.020Gaia, so great to be with you today. Very excited to talk about this. It's a topic that we've
00:03:56.040discussed a number of times on the podcast, but unfortunately, there's always a lot to talk about
00:04:01.720here. And I think you're a physician that, of course, is near and dear to our heart in the
00:04:09.200practice. We co-manage a number of high-risk patients. And I've just always been impressed
00:04:15.060by the way that you have taken a very personalized approach to managing this condition. But I just
00:04:20.480want to let folks get to know you a little bit better. So you're both a neurologist and a
00:04:26.560psychiatrist. Is that correct? That's correct. I mean, I'm boarded in multiple specialties,
00:04:31.320neurology, psychiatry, brain injury medicine, pain medicine, and behavioral neurology. But
00:04:38.480my subspecialty is really memory disorders, primarily from a neurological perspective.
00:04:44.060But all these other areas allow me to better handle people with cognitive impairment.
00:04:50.060I'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 dementing conditions that we're going to talk about today?
00:05:12.200I think two things, Peter. One, that over the years of my practice, I've come to realize that pretty much all dementing conditions, and particularly Alzheimer's disease, can present variably depending on the person who has the condition and also depending on comorbidities.
00:05:39.140So there really is a spectrum aspect to Alzheimer's and dementias, which people don't recognize.
00:05:46.740They think of it as an all-or-nothing disease, and that's not true.
00:05:50.240Much 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.
00:06:01.540That's number one, that dementias are really a spectrum disorder.
00:06:05.640And 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 and after penicillin was invented, you know, or discovered, sorry.
00:06:23.620So basically that there are now so many different ways that we can treat dementias, we can personalize our treatment, we can give each person the right cocktail, if you will, of medications that would best benefit them.
00:06:41.980And we now have drugs that can alter the course of the disease, which is absolutely, to my mind, fantastic.
00:06:50.080We still have a ways to go, but I feel like we're on the threshold of something really grand.
00:06:56.660Well, that's probably the thing I want to talk most about today, but 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.
00:07:13.280So we're going to talk about some of these risks and then the various treatments around them.
00:07:17.000But 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.
00:07:23.420It's not like you have vascular dementia or you don't, or you have Lewy body dementia or Alzheimer's disease or you don't.
00:07:30.200Can you go a little deeper into this idea of what the spectrum of these diseases look like?
00:07:34.660And maybe for the purpose of this first question, let's limit it just to Alzheimer's disease.
00:07:40.920So maybe define Alzheimer's disease within the broader context of dementia.
00:07:45.500I think there's probably still some people who use those terms synonymously, even though
00:08:23.460And there are several different types of dementia, Alzheimer's being the most common.
00:08:28.060And what Alzheimer's is defined as is a loss of synaptic connections,
00:08:33.320or synaptic connectivity that results in a loss of function that is driven by the presence
00:08:43.880of extra neuronal amyloid plaques, intra neuronal or intracellular tangles, neurofibrillary
00:08:54.040tangles, and increasingly what we now know to be inflammation in the supporting microglial
00:09:01.500cells and other glial cells of the brain substrate that cause cognitive impairment that progresses.
00:09:09.880So the question is, how do you make this diagnosis in a person? And, you know, that's really
00:09:16.800difficult because you have to really have a high index of suspicion, particularly with people who
00:09:26.880are very intelligent, people who are very functional, people who are able to compensate
00:09:32.440very well, so that you can have someone who has moderate pathology and even severe pathology,
00:09:40.960and they can still perform very well in many areas because they have a good brain reserve.
00:09:48.800They have a resilience in their brain that prevents the kind of cognitive and functional
00:09:53.880deterioration that someone who has less reserve and less brain resilience doesn't have. And there
00:10:01.480are many different subtypes of Alzheimer's disease, depending on the part of the brain that's
00:10:07.080affected. So you can have an Alzheimer's disease that primarily affects memory versus Alzheimer's
00:10:15.620that can affect more the visual-spatial system. So it depends on the area of the brain where the
00:10:22.360pathology tends to predominate. And it also depends on secondary conditions, comorbid brain
00:10:30.220conditions that are present, such as Lewy body disease, TDP-43 pathology, agoraphilic brain
00:10:37.960disease, all of which can inform how the person presents. So when you're looking at Alzheimer's
00:10:44.880disease, you want to look at, first of all, you want to establish that the person has these
00:10:50.440plaques and tangles. And that's something we can get into later because there are two groups
00:10:56.220of thought on that. There are people who say, well, you can just have biological indices that
00:11:03.520say that a person, you can diagnose Alzheimer's just based on biological biomarkers alone versus
00:11:10.940another group that says, well, no, you need biomarkers plus clinical symptoms. You need
00:11:16.500biomarkers plus functional deficit to make the diagnosis. But the biomarkers are really amyloid
00:11:23.140tau and increasingly neuroinflammation. Okay. A few things I'd like to unpack there,
00:11:30.860but maybe I actually want to start with a more basic question, which is we will get to obviously
00:11:38.140talk about APOE, the genotype, which is probably one of the most common genetic predisposing factors,
00:11:45.160although not the strongest. And maybe we can even spend a minute talking about the other
00:11:49.040genetic conditions that are more dispositive in their prediction of a person developing
00:11:53.880Alzheimer's disease. But pathophysiologically, what is the order of operations? Stated another
00:12:01.520way, what starts this process? Does it start with the inflammation? Does it start with the
00:12:08.240deposition of amyloid? Does it start with the tangles? Is it different in every person? Is
00:12:15.340it different by location in the brain? Maybe talk us through that a little bit.
00:12:20.300So generally speaking, it used to be thought that really amyloid was the first abnormality
00:12:26.640that begins in the brain up to two to three decades even before the onset of clinical
00:12:34.520symptoms. But now we're beginning to understand that changes in the inflammatory pathways may
00:12:41.860predate amyloid deposition by quite some time. So it may be that first neuroimmunological changes,
00:12:51.500then amyloid, and then eventually down the road tau, and that ultimately causes synaptic
00:13:00.500dysfunction where the synapses, the connections between the nerve cells start to go awry and the
00:13:07.420person then develops cognitive changes. And that process takes decades. So the whole point, I think,
00:13:14.640with Alzheimer's and other dementias is if you can intervene early enough, even as early as your
00:13:22.08030s into your 40s by incorporating anti-inflammatory methodology, anti-inflammatory
00:13:29.920activities into your lifestyle, then perhaps you can prevent the whole cascade from being triggered.
00:13:38.020On that topic, one of the things we've become much more aggressive in our practice around
00:13:44.140is managing two viruses in particular, herpes simplex virus and varicella zoster.
00:13:51.020Now, 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 by the time you're 50 is virtually everybody.
00:14:07.680And so presumably the observations that we see that there's a significant reduction in the risk
00:14:15.620of dementia and Alzheimer's disease in people who have been vaccinated for shingles and people who
00:14:22.100have HSV treated suppressively versus those who don't. The thinking is that this works through
00:14:28.880an inflammatory pathway. What can you say about any of that? Yeah, I really think there's something
00:14:34.980to be said. I think neuroinflammation is going to be the new frontier in terms of how we're going
00:14:40.600to deal with and even prevent entirely Alzheimer's disease. I have, for example, like two patients in
00:14:48.400my practice where the sibling is riddled with Alzheimer's, but these two patients have severe
00:14:57.080neuroimmunological disease that they've been treated with aggressively for decades, and neither
00:15:03.600of them have a lick of Alzheimer's pathology. It's quite impressive. So I think there's something
00:15:09.740to be said for, you know, this kind of treatment with an exposure to various viruses that have a
00:15:17.520predilection for the brain and the central nervous system, like the herpes zoster virus, for example,
00:15:22.800that causes shingles. Sorry, just to clarify the case you presented there, are you saying you have
00:15:28.300three siblings that are genetically comparable? I mean, meaning like they would all have the same
00:15:32.860ApoE phenotypes across them, they're 3-4s or 4-4s or whatever. One of them has disease. The two that
00:15:38.920do not have a deficiency of their immune system that renders them less susceptible to mountain
00:15:46.300immune response? So I have two pairs of siblings. Ah, okay. So in each of which one sibling has
00:15:54.780significant Alzheimer's and the other sibling doesn't, which is particularly remarkable in one
00:16:02.180case because that person has two copies of the APOE4 allele, which puts them at higher risk,
00:16:09.540in fact, definite risk for developing Alzheimer's. And that person doesn't even have any amyloid,
00:16:15.460not even a touch of amyloid in their 70s. So it gives you pause. It makes you think,
00:16:20.420well, what is it about this person that protects them?
00:16:24.440And are you saying that they have a known immunologic condition that is reducing inflammation,
00:16:30.120or are you saying that's the hypothesis potentially?
00:17:32.640And to your point, even the entire gastrointestinal system, you know, the internal lining gets
00:17:37.640replaced, what, every two weeks, the entire lining does.
00:17:41.420So you've got to think what happens in that process and how that drives, you know, that
00:17:46.680changes with different immunological conditions.
00:17:51.840So talk to me about how you evaluate a patient.
00:17:54.860Let's maybe take a step back and talk about your practice.
00:17:56.940So are patients coming to you more commonly being referred by another physician? Are 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?
00:18:15.820we have i've been in my practice on the upper east side for 26 years so over this time there's
00:18:24.980a large a referral base of physicians who refer to me i also have kind of developed a niche in
00:18:32.700terms of the evaluation and treatment of physicians and other professionals so they seek me out they
00:18:40.160read an article in a journal or something along those lines. And then, of course, referrals through
00:18:46.100families and friends. The one thing I will say about our practice is most of our patients
00:18:51.580are highly functional. They're still working, many of them, and they want to stay working.
00:18:58.220And my great joy in these years is that I've been able to help them achieve that goal,
00:19:06.360to be able to stay functional and useful to the society and also have a sense of agency
00:19:12.900for themselves. So the thing, the challenge with all these patients, especially the high
00:19:19.680functioning ones, is that they are extraordinarily, their brains are extraordinarily smart at
00:19:28.420compensating. So a lot of the testing that we do has to be fairly rigorous in order to uncover
00:19:35.680the problems that such patients might have. So if you did like what people routinely know,
00:19:41.800which is the mini mental status exam or the MOCA exam, many of these patients score a 30 or 29 or
00:19:48.00028 well along into their condition, even 10, 15 years into their condition because they are so
00:19:55.900adept. They have such great cognitive reserves. What do I mean by cognitive reserve? The ability
00:20:02.380of the brain to maintain a large number of connections and to be resilient to disease
00:20:12.680So once we put them through, so first of all, we do a very meticulous general history, including
00:20:19.360history about immunological conditions, past exposure to shingles, things like that, family
00:20:25.600history, and then after that decide on the kind of testing we want to do, which often
00:20:31.400involves cognitive testing, which takes several hours. We often will look at the electrophysiology
00:20:37.960of the brain to see if there's any evidence of early slowing. Look at brain blood flow using
00:20:43.940transcranial Doppler to see how much blood flows through different areas of the brain. We will do
00:20:49.380specialized exams, imaging exams, such as MRIs, using special techniques so that we can evaluate
00:20:58.300the different brain regions, such as the hippocampus, the parietal lobes, so we can
00:21:03.440see if there's differential changes there, early changes. And oftentimes, especially here in New
00:21:09.700York, we're able to do amyloid scans and people that we're worried about, and tau scans, which
00:21:17.220measure brain levels of tau, which is the other abnormal protein that's associating Alzheimer's.
00:21:22.340And 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.
00:21:35.060So it's a fairly rigorous series of tests that's tailored to each individual person.
00:21:40.720And of course, laboratory testing, looking at APOA, APO little b, inflammatory markers,
00:21:51.200And certain patients where there's a history, family history of early onset Alzheimer's,
00:21:56.140we do do early onset genetic screening to see if there's a particular gene that's abnormal.
00:22:02.560And how routine is the use of a lumbar puncture? Is that something you would do in everybody or
00:22:08.800has the robustness of the current blood-based biomarkers for AB 4042 and P-tau displaced a
00:22:17.120lot of the need for lumbar puncture? So I am kind of, I think I'm old school
00:22:22.060with the blood-based biomarkers. I definitely think they are the future, but I'm not sure
00:22:28.100they are already the future. I feel that they are standardized against amyloid, for the most part,
00:22:39.020amyloid scans. And I'm of the opinion that they would probably need to be standardized against
00:22:45.240both amyloid and tau, because so many of us in our 70s and 80s have amyloid and will never
00:22:53.180develop Alzheimer's. So I tend to, pretty much in any one that I'm concerned about with Alzheimer's,
00:23:01.760I will do either tau and amyloid scan or a spinal tap. The advantage to the spinal tap is it's less
00:23:10.940expensive, and you also are able to detect very early changes in tau, whereas the tau PET scans
00:23:19.320traditionally don't really pick up early changes in tau. The disadvantage, of course, is no one
00:23:25.320wants to get a spinal tap. Although, may I just say that all the women who've had epidurals to1.00
00:23:31.820have children have effectively had reverse spinal taps. You know, they've had anesthesia injected
00:23:37.220into their spinal cavity. That workup sounds incredibly extensive. On average, since you're
00:23:44.300managing this is patients who are outpatients. You can't do everything you just said on a day,
00:23:49.520I'm imagining. So is that, for a motivated patient, is that a week, two weeks worth of
00:23:55.860interventions? So we have patients come in from around the world or from different parts of the
00:24:03.200country, and they're just here for testing and an evaluation. And we're able to pretty much
00:24:08.160schedule everything over a two to three day period. Okay. That is an exhaustive list of
00:24:14.800tests. I'd love to kind of walk through the contours of how you piece together results
00:24:22.220and start to come up with what the archetypes are. So in other words, once you have all of
00:24:29.620those tests back, how do you start to say, this is the pathology. So let's call it by disease.
00:24:37.060So 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?
00:25:01.480And basically, how do you take that information and then create a treatment plan?
00:26:21.020This 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, then it may affect how well they're going to be able to function.
00:26:34.820And that's one of the ways I assess in a single time point how much of a change has occurred.
00:26:44.080So someone whose overall ability at the 99th percentile, visuospatial skills at the 10th percentile, language skills at the 10th percentile, I worry that this person's declined quite a bit, but they're compensating overall.
00:26:57.420And maybe the following, the ensuing year, might be a year where they're losing quite a bit of function.
00:27:03.460So this might be someone where you want to be more aggressive about treatment.
00:27:08.440You have a patient who's having problems with language, and they have just in that area,
00:27:13.100their blood flow is much reduced, or they have some slowing in their EEG, which is worrisome,
00:27:19.440even though they look clinically fine.
00:27:21.700All those things go into, all those different facets of their evaluation go into my final
00:27:28.820determination of how much of each condition. Often it's very rare that the person just has
00:27:36.100primary Alzheimer's alone. They'll usually have Alzheimer's plus. Alzheimer's plus a little bit
00:27:42.520of stroke. Alzheimer's plus a little bit of hydrocephalus. Alzheimer's plus a little bit of
00:27:48.540TDP-43 pathology. So you want to kind of put that all together and see how much each area is being
00:27:55.340affected. Interestingly, if it's only memory that's being affected, that's actually a better
00:28:02.040prognosis for patients than if it's primarily language that's being affected. Because we have
00:28:07.980data to show that the trajectories, the rate of progression varies across depending on where the
00:28:15.560pathology is. And then I'm not, I'm one of those people, I think, who is very, very, very averse
00:28:23.360to staging Alzheimer's. I am not, people often will say to me, well, what stage is this person
00:28:30.280in? And I usually say, listen, this person is at stage zero as far as their ability to communicate.
00:28:37.680But maybe in memory, they're at a stage three or four. And maybe in language, they are in a
00:28:44.660different stage. So you really want to look at the person in all their different functional domains
00:28:50.980and stage them on their different domains, that helps you better than just giving an overarching
00:28:57.480stage, which I find to be very reductionist, simplistic, and does a disservice to both the
00:29:04.100patient and the family. I want to ask you a question that I am positive you get asked every
00:29:10.360time you go out and someone finds out what you do for a living, which is what explains the fact
00:29:16.860that I might be seemingly in perfect neurological health and yet I find it very difficult to
00:29:26.580remember names of people who I know and I don't mean like know very well like my wife or my kids
00:29:32.440but like a person who I've met 30 times I might see them for the 31st time and it might take me
00:29:40.520a full minute to remember their name so people ask me this all the time because they experience it
00:29:46.760and truthfully I observe it in myself a number of times and it's not just the name of an individual
00:29:51.820it could be I don't know like the name of a city or something like that it just happened to me the
00:29:59.840other day I couldn't remember Ibiza I was like what is that place in Spain again where everybody
00:30:07.620goes to party and it literally took me it felt like an hour it was probably 15 seconds but it
00:30:14.160was an eternity to come up with Ibiza. Like, I don't know how I could forget something like that.
00:30:18.840So again, I don't believe that I have Alzheimer's pathology, but what explains this phenomenon of
00:30:26.340occasional delays in acquisition of names? This is, you're right, one of the most common
00:30:33.880questions that I get asked and one of the most common requests. Will this treatment help me
00:30:40.120remember better, particularly nays. And I always say, get used to calling people darling and dear.1.00
00:30:47.000Become more Southern, you know, because the truth is names are inorganic bites of information. Our
00:30:54.280brain is trained to remember things organically. So a name is really a neologism. It's a made up
00:31:02.520thing. It doesn't have very much meaning. And we're now, particularly in modern times, obviously
00:31:08.600inundated with names, whereas 100 years ago, there were very few names that one had to remember.
00:31:16.620There are certain people who have a proclivity for remembering names, politicians, for example,
00:31:21.580someone you might know who never forgets a name. But the vast majority of us, our brains are not
00:31:28.320meant to remember an endless amount of names. We really, maybe, I mean, some people speculate that
00:31:34.680Maybe we're only supposed to remember 150 names, which is a very small amount.
00:31:40.720I would say that the majority of us have access to most names, and 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.
00:31:57.840The other issue, which I think is more problematic, is the ability to recall common nouns.
00:32:04.680To remember to call something a chair, to say, well, that's a book.
00:32:09.340I want to know the five different ways you can say green, you know, chartreuse, taupe, taupe, hunter green, et cetera.
00:32:17.640Those kinds of things, if you're beginning to have trouble coming up with finding words for that, finding words as opposed to trouble finding names, that becomes more of a problem.
00:32:29.700Because 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're well rehearsed, like the names of your family members, are much more episodic.
00:32:48.420Their names are more like episodes, triable, things that happen that have a specific time and place.
00:38:36.280They often have more language difficulty problems than men do.
00:38:41.180Men present more often aggression with agitation, and so the presentation is different as well.
00:38:48.760And what about the pathologic findings when you get right down to the assessment?
00:38:54.600If you took a man and a woman who would ultimately turn out to both have Alzheimer's disease,
00:39:00.220are you going to see differences in the patterns of amyloid versus tau
00:39:05.100versus any of the other markers that you're looking at as sort of standard markers?
00:39:10.420Generally 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.
00:39:31.620And also women who present with Alzheimer's tend to generally have gone through earlier menopause, tend to generally not have been on hormone replacement.
00:39:42.360Yeah. 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 WHI in 2002.
00:40:01.680And 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.
00:40:21.880We 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.
00:40:34.720So I think people nowadays, meaning patients themselves, are even requesting, hey, you know, Doc, can you look at my AB4240? 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.
00:41:02.900May I talk a little bit about the differences in diagnostic approach here?
00:41:09.380Okay. So I'll actually tell you a story. I saw a patient in the early part of last year
00:41:15.980who just had, you know, is a high-functioning man who had, in his 70s, kind of vaguely wasn't
00:41:23.420feeling well, ended up seeing a neurologist who I really respect at an academic center here in
00:41:30.260the city and got tested for, he actually happened to get the Quest testing for AD detect tests
00:41:38.140to see, and it turned out he had abnormal levels of A-beta 42 and therefore was diagnosed with
00:41:48.320Alzheimer's by this neurologist. And he came to me for a second opinion. My feeling was, you know,
00:41:55.640after talking to him, I wasn't really convinced that he had really cognitive impairment. I thought
00:42:01.340he felt a little slow, a little sluggish. Maybe there were physical issues. But be that as of May,
00:42:07.840we did amyloid scan and the scan was negative. So for about three weeks, he had thought he had
00:42:14.400Alzheimer's. He didn't have Alzheimer's just based on the scan alone. So I'm saying this
00:42:19.580as a cautionary tale to say that you want to be careful making a diagnosis of Alzheimer's with
00:42:27.160just the blood tests alone. I mean, there are certain blood tests, the LumiPulse blood test,
00:42:32.860the Percivity blood test, the Quest AD blood test, the C2N assays. But all these are generally,
00:42:41.080all the blood tests are standardized against, for the most part, I think there are a couple that
00:42:46.740aren't, but the ones I mentioned are all standardized against amyloid beta pathology
00:42:53.100on PET scan. So because amyloid is present, so if you take all people in their 70s,
00:43:03.720community-dwelling people, and you image them, about 25% of us will have amyloid in our brain.
00:43:10.240If you take people in their 80s and you image them, about 30-plus percentage of us will have amyloid.
00:43:17.860And by the time you get to 90, about 44% of us will have amyloid without symptoms, living in the community.
00:43:25.760So 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,
00:43:36.880In other words, when it's positive, it means it really is Alzheimer's, not another condition.
00:43:41.140But you're validating it against an amyloid PET test, PET scan.
00:43:46.540You see my problem there, is that because amyloid is positive in so many people as we
00:43:53.660get older, many of us without any clinical symptoms, what does this really mean?
00:43:58.960And so this is now a critical juncture, I think, in terms of how we diagnose Alzheimer's,
00:44:05.680Because there are two groups that have different approaches to diagnosing Alzheimer's.
00:44:11.440That is the Alzheimer's Association criteria for diagnosing Alzheimer's, which diagnoses Alzheimer's primarily based on the presence of amyloid, whether it's in the blood, whether it's in the brain.
00:44:24.620And there's the International Working Group, which is mostly European, but international.
00:44:30.460A member of the National Institute of Aging is a part of it.
00:44:34.240a few American major centers are a part of it as well. That group feels that there are too many
00:44:42.940people who have amyloid so that when you make a diagnosis, you really want to be sure that you
00:44:49.720have amyloid and tau and symptoms. So it's a clinical biological condition rather than a
00:44:58.260primarily biological condition. So I'm careful about testing people who are asymptomatic unless0.99
00:45:05.180they have a family history. So for example, I have a young physician in her 50s, both her parents had
00:45:11.700Alzheimer's, confirmed Alzheimer's, and she has two copies of the four. She's somebody where you
00:45:17.920really want to do testing, even though she has no symptoms, right? And she turned out to have
00:45:23.560amyloid in her brain and she's being treated to clear the amyloid. So there is, I think, a role
00:45:30.220for preclinical testing in people who are at high risk, but the vast majority of people, we should
00:45:36.320be careful. And if the blood tests are positive and it's surprising, you may really want to get
00:45:42.940further testing to confirm the diagnosis because otherwise, as the International Working Group
00:45:49.060very eloquently put it, you have a large population of, quote, patients and waiting,
00:45:55.660unquote, people waiting to become patients, but maybe in the process changing their whole approach
00:46:00.860to living. You've got to be careful. Yeah, this is, to me, what separates this type of screening
00:46:06.700from cancer screening. Obviously, I'm very vocal about my view on early and aggressive cancer
00:46:12.580screening, and I certainly take a lot of criticism for it, but I find it very easy to defend the
00:46:17.320position and I won't do it now. However, I think the type of screening you're describing is
00:46:23.440fundamentally different, not only because of the pretest probability, but because of the implications
00:46:30.260of what to do about it. And so I think your approach makes a lot of sense. And unfortunately,
00:46:37.920yeah, go ahead. Just to go back to your cancer analogy, when PSA screening first came out,
00:46:45.140you know, a while back. The incidence of patients being diagnosed with prostate cancer just rose
00:46:51.840dramatically. And it was only a few years later that we were able to approach it in a more nuanced
00:46:58.300way and understand that PSA levels rose as we get older. So you really want to plug all the factors
00:47:05.900in rather than just knee-jerk, oh, high PSA equals prostate cancer. You got to figure out age, etc.
00:47:12.280And 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.
00:47:23.980So 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.
00:47:36.700So the example you gave is a highly functional woman in her 50s who carries two copies of
00:50:22.560So whenever people say they have Alzheimer's, I actually, in my family history, write down
00:50:27.560that the person has a family history of dementia, but we don't know what type it is because
00:50:32.820most often they may not have had Alzheimer's.
00:50:35.680But in this physician's case, because I also happened to take care of her father, I know
00:50:41.000that he really did have Alzheimer's because we've done all the tests, the amyloid and
00:50:45.420the PET scan. And the mother who had died did not have an autopsy, but most likely had Alzheimer's
00:50:52.340as well, based on her presentation. So in her case, even though she did very well overall,
00:50:58.940she may have had a couple of areas that I was not quite happy with on the cognitive scores,
00:51:05.480you know, things that gave me pause. Her language wasn't quite as fluent. Maybe there were a couple
00:51:10.300of areas where her memory could have been better for a physician compared to her overall ability,
00:51:15.600which was quite high. And therefore, we opted to start her on a whole slew of preventive
00:51:23.500treatments to help her reduce weight. She went on a GLP-1, but she also went on a monoclonal0.97
00:51:30.480antibody to remove the amyloid that was beginning to build up in her brain. And I think that was
00:51:36.440something that I was very excited to do with her, that she was very excited to embrace because now
00:51:43.480there was a possibility that we could change her destiny, you know, and, and that's really the kind
00:51:49.980of thing I find wonderful. Okay. So let's, let's talk about these anti-amyloid therapies because
00:51:56.800they're a little bit of a mixed bag. In fact, I don't know the order, but was aducenumab the
00:52:03.980first one that was approved? Yes. Okay. And gosh, it's, it's hard to believe how fast time has
00:52:09.400flown, but I want to say it's been, was this pre, this is probably about six or seven years ago.
00:52:15.900So adacanamab, I can tell you exactly when adacanamab was approved in July of 2021.
00:52:24.500Oh, wow. It was post COVID. For some reason I thought it was pre COVID, but,
00:52:27.500But it was a very controversial approval in the scheme of things because there was an advisory board to the FDA that recommended against approval.
00:52:48.140But in this case, it did, and it went ahead and approved the drug.
00:52:50.680So walk us through the controversy there.
00:52:52.700Why did the advisory board say one thing and the FDA another?
00:52:55.140The advisory board was not—so the adecanumab, 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, lakanumab, lakembi, and donanumab, kisunla.
00:53:16.460All 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.
00:53:30.460The 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 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.
01:00:13.240The example I would give here is it's a drug that lowers LDL cholesterol but doesn't prevent heart attacks.
01:00:20.200You 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.
01:00:30.000A, we could be looking at too short a period of time.
01:00:32.380B, we could be looking too late in the history of the disease. If we intervene earlier, give
01:00:39.240ourselves more time and mitigate the side effects by ramping the drug up slower, we are after all
01:00:45.160removing amyloid and amyloid is playing a role in the disease. Is that a fair assessment of the
01:00:50.480nuance that you sort of applied to the first drug, which is no longer there, but the logic still
01:00:55.140applies to the second and third? That's correct. Yeah, exactly right. And the other thing, Peter,
01:01:00.740I always ask myself anytime a new drug comes out is, would I want this drug? If I had Alzheimer's
01:01:07.860now, knowing everything I know about this drug, would I want to be on this drug? And I felt that
01:01:13.100with adecanumab, my answer was yes. So that's why I started giving it to my patients. Now,
01:01:19.080was it ultimately pulled off the market because of area or was it pulled off the market because
01:01:24.440of lack of efficacy? It was pulled off of the market because they required post-monitoring
01:01:33.780of the drug because of the controversy, and that became financially for the company, I think,
01:01:39.200unfeasible. Got it. What is the annual cost of lacanumab and decanumab?
01:01:45.080The drugs themselves cost about $26,000, but then there's the administration fees,
01:01:52.300which can range, you know, sometimes in institutional settings, they can be as high
01:01:56.900as $10,000 just to infuse the drug versus you go into a infusion center, it could be $400. So
01:02:03.760there's always that spread per infusion. And then there's a cost associated with the MRIs that the
01:02:10.520patients might need, which they need, and then they need amyloid imaging. And one of the things
01:02:17.100that I unfortunately have discovered is the insurance companies, especially with lukanumab,
01:02:22.560which starts at 10 milligram dosing right away, 10 milligram per kilogram, they will not reimburse
01:02:28.880patients if we start them at a lower dose and titrate them up. So in other words, your efforts
01:02:35.680to protect the patients from area-related imaging abnormalities is something the insurance companies
01:02:42.760are saying, hey, we don't have a protocol for this. So the patient's going to have to pay out
01:02:46.720of pocket if they want a safer protocol. That's correct. Yeah. That sounds about right.
01:02:51.720We haven't run into, yeah, it's very unfortunate. We haven't run into that with the donatumab so
01:02:56.920much because donatumab does have a 350 to 700 to 1050 to 1400 milligram titration schedule.
01:03:05.440And so we've been able to like keep people at the 350 for like four or five infusions without
01:03:11.040anybody noticing. But unfortunately, we haven't been able to do that with lakanumab because it
01:03:15.660just starts at 10 milligram per kilogram. And we've had patients, Peter, who are 4-4 patients
01:03:22.780who've had severe aria on just three milligrams of lacanima, three milligrams per kilogram,
01:03:30.520as opposed to the 10. So can you imagine what their side effects would be on 10 milligrams
01:03:35.320per kilogram? And the reason for this is simply the higher initial risk. In other words, it's
01:03:42.240It's that the APO, if you're a 3-4 and then ultimately a 4-4, with each of those steps,
01:03:47.140you're moving towards a higher susceptibility for the edema and or the hemorrhage in response
01:06:18.800So we have a very rigorous monitoring protocol with imaging.
01:06:24.300And I will say I've been using monoclonal antibodies since 2021, so it's been over five years.
01:06:30.280And I would say I cannot remember, perhaps in one 4-4 patient who was in her early 60s with Alzheimer's, she had some visual findings.
01:06:40.800But everybody else, we only discovered the brain bleeding and the brain swelling on MRI.
01:06:48.800Sorry, 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?
01:07:06.360I did have one case, which was a drug.
01:07:09.540And all the patients have stayed on the monoclonal antibody, including one patient who had significant aria, where he had arias defined in multiple places, some of them rather large, aria-y.
01:08:17.000And he, what we did was we realized that the aria had happened a few weeks before because
01:08:27.220of the characteristics on the MRI, it wasn't acute. And he actually happened to, wanted to go to
01:08:34.040Europe the following week. His exam was normal. So he went to Europe and then he came back and we,
01:08:40.680I think we cut down to a lower dose. We went down to six milligrams and then went back up again.
01:08:46.580So it was a scary moment. What I do do now, what I've learned to do is when you have patients who
01:08:53.840have people with CAA, cerebral amyloid angiopathy, can have ARIA without, as I said, without any
01:09:01.880impetus. They can just have spontaneous ARIA A and E. And generally the way you treat it
01:09:09.560is you treat it with steroids. So what I do in my patients who have, like for example,
01:09:16.840this young woman who's got 4-4 and 3 lakanumab, 3 milligrams of lakanumab, who has ARIA-E,
01:09:25.560which seems fairly refractory, I treat her with steroids as you would somebody who has
01:09:31.460cerebral amyloid angiopathy with the inflammation. And we just pre-medicate with steroids,
01:09:37.980and that seems to control it. Ah, pre-medicate. So in other words,
01:09:42.500you're saying you prophylactically manage with a small dose of a steroid before each subsequent
01:09:47.400dose once you've made the diagnosis of RNA. So are there any clinical trials that are going on
01:09:55.200to take this protocol of yours and do it in a randomized fashion? Because obviously you're
01:10:00.920doing it in what we would call open label, meaning everybody is being treated this way. Nobody's
01:10:05.300getting either a placebo or a standard approach. To me, an elegant trial, quite frankly, although I
01:10:12.260think it would be cost prohibitive, and that's probably why it's not going to be done, would be
01:10:16.480taking your low and slow approach, what I would call the low, slow, early approach, right? So we
01:10:24.120take these high risk patients that are in their fifties or sixties, who are probably 10 years
01:10:29.680away from clinical disease or five years away from the first symptom. We treat them in a way
01:10:35.000that is very low, very slow, very safe. And we ask the question, are we bending the course of
01:10:41.480their disease. Because to me, that's the interesting question, right? I think what
01:10:45.280these drugs have demonstrated is if you take a person who is in florid dementia and you slam
01:10:52.200them with these monoclonal antibodies, you are not bending the arc of their life. And in fact,
01:10:59.080if they are E44, you are introducing a staggering amount of risk. In fact, I assume many neurologists
01:11:06.160would not even treat an E44 late enough in the game with a high enough dose because the risk and
01:11:11.780reward isn't there. So it's a shame that, you know, the companies that make these drugs wouldn't
01:11:18.640subsidize the cost in a way that would allow a more longitudinal study in what I think is the
01:11:23.840appropriate patient population. But, you know, I'm not going to diminish the cost of monoclonal
01:11:29.420antibodies. They're certainly more expensive than your typical small molecule, but they're probably
01:11:33.700not the sticker price. And I think there's more people to be helped if we could do the right
01:11:38.880study and again, kind of replicate what I think you're doing clinically. Because again, the
01:11:43.520approach makes sense. If you think about most chronic diseases, time and area under the curve
01:11:50.040is the issue, right? We know this with atherosclerosis. If I take a person for primary
01:11:56.720prevention, I'm not going to move the needle treating them for a year. It's just not enough.
01:12:01.900I 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, you know, with every drug, whether it be GLP-1s or statins or any drug, they always get better with subsequent generations. So where do you see them going next?
01:12:23.620I think we're going to have drugs that are monoclonals that are able to like ameliorate this risk of, you know, edema and hemorrhage, drugs that can be taken as pills, drugs that can be given at home.
01:12:39.580And 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 in a, you know, a television show in which we were discussing Alzheimer's.
01:12:55.280And so she came to the office and she turned out to have Alzheimer's as she's very, very, very functional, not particularly.
01:13:03.260I mean, I think her overall ability was at the 70th percentile, so not, you know, one of these
01:13:08.960uber high-achieving people. And we started her on medication after a spinal tap showed evidence of
01:13:17.500amyloid and tau. And she was on the CanMab. She eventually cleared the amyloid. I decided to do
01:13:26.360a tau scan. She no longer had tau. And, you know, there is downstream reduction in tau in all these
01:13:35.220different, with all these monoclonal antibodies, because even though they target amyloid, they also
01:13:40.560clear some tau. But she actually had no tau on her tau scan. So now we're waiting on her spinal tap
01:13:47.640because I refuse to believe that we've basically erased, removed her pathology. Clinically, she's
01:13:54.720done remarkably well. So again, speaking to the spectrum of Alzheimer's, there are some patients
01:14:00.220who respond dramatically. And who knows, maybe her immune system is just different from someone
01:14:06.680else. I have a pair of identical twins, and I take care of one of the two. And the one, she just,
01:14:13.340you know, she was on a monoclonal antibody, initially on adecanumab and then on donanumab.
01:14:19.260And she did much better than her identical twin, who was in a facility.
01:14:25.400And my patient actually also had heart disease.
01:14:28.120She had rheumatological heart disease, which destroyed her valve.
01:17:09.540Many patients may benefit from interventions like ventricle peritoneal shunt for hydrocephalus.
01:17:18.480And the other area that I feel is important is maintaining a person's neuronal connectivity.
01:17:26.240And by that, I mean how well the networks function.
01:17:30.820And for that, in 2008, I started using transcranial magnetic stimulation, targeted TMS, to help maintain function.
01:17:39.920And TMS works by stimulating the brain using magnetic stimulation that then creates a small area of current just under the area of the coil.
01:17:54.340So an area about one centimeter squared of the cortex gets stimulated, and then that creates a stimulation in the circuitry to which that area of the cortex is attached and connected.
01:18:06.740And 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.
01:18:22.460And 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.
01:18:39.180I 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.
01:18:49.180I really always use TMS using neuronavigation guidance of anatomical structures. So we actually have kind of a, we plug in the patient's 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.
01:19:09.160And I usually stimulate the dorsolateral prefrontal cortex, Broca's area, the precunias for parietal and visuospatial skills.
01:19:18.680And some patients, we also stimulate the auditory Wernicke's area.
01:19:24.760And again, this is off-label because TMS is only approved in the United States for treating depression and for certain electrodiagnostic purposes.
01:19:33.380But we've been using it off-label since 2008 for treating our patients with dementia.
01:19:41.020How optimistic are you on the causal nature of the relationship between GLP-1 agonist
01:20:00.820You 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.
01:20:18.920But 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?
01:20:32.760I believe so. I think the GLP ones offer an advantage. And even the older drugs like metformin, you know, may offer benefit in this area. And so I do use it in my patients where I think it's necessary.
01:20:47.940And, you know, the other thing, too, is obesity is finally coming down in the United States, you know, tax the GLP-1s.
01:20:56.120And 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, diabetes.
01:21:11.580We've talked a lot about Alzheimer's disease.
01:21:13.600I do want to just give a little bit of time to discuss vascular dementia and Lewy body
01:21:18.900dementia, and I'm assuming you see quite a bit of those in your practice as well.
01:21:22.780Can you walk us through, A, how those diseases present, and B, how you diagnose them?
01:21:31.280Alzheimer's almost never presents in isolation.
01:21:35.160So they've done autopsy studies in patients and find that between 98% to 99% of patients with Alzheimer's have some kind of concomitant primary brain pathology.
01:21:50.500And the most common is vascular disease, vascular brain disease.
01:21:56.060But in terms of the primary vascular dementia, I find that rarer than you might think because so many of us as we get older will have some vascular disease in our brain, what I call white matter schmutz in the brain, and used to be thought of as rather benign.
01:22:15.780but now we know that it is not benign, that it interrupts the connectome of the brain,
01:22:21.180and it's progressive and causes problems that perhaps interfere with the resilience of the
01:22:27.680brain to pathology and therefore needs to be addressed specifically. So I'm fairly rigorous
01:22:34.620about treating patients with vascular dementia, often with concomitant other conditions as well.
01:22:41.540And 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 that they do have atrial fibrillation or some kind of a heart problem that is the cause of the strokes.
01:23:04.340I recommend a watchman so that they can then go off the anticoagulant medication,
01:23:12.860Eliquis, Xeralto, et cetera, because many of these patients are at higher risk for falls
01:23:21.620They have dementia, so it just prevents an added problem down the road.
01:23:27.660Along those lines, in patients who are on blood thinners for atrial fibrillation or another condition, who 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 anticoagulant and then get on the monoclonal.
01:23:54.940So I've done that with a few patients.
01:23:57.320Lewy body disease, you know, if you look at patients with Alzheimer's, about 40% of
01:24:02.140them eventually will have some level of Lewy body pathology.
01:24:05.700If you look at patients with Lewy body, about 30 to 40% of them have Alzheimer's pathology.
01:24:11.700And so some people think even a higher number.
01:24:14.040So the two conditions coexist quite a bit.
01:24:16.900What I find the most troubling in my practice is the number of patients with Lewy body who get diagnosed as having Parkinson's and therefore are treated with Parkinsonian medications, levodopa and carbidopa, the dopamine agonists like Meropex, et cetera.
01:24:38.840And that actually worsens their Lewy body.
01:39:00.180You did. I'm very impressed. How did you remember that?
01:39:03.420I have a great team of analysts that remind me of these things. So is there ever a scenario where you have a woman who's come to you, she's got a history of breast cancer, and you're just saying it's not worth the risk, or she's too afraid of the risk?
01:39:22.260you may or may not be familiar with my views on the relationship between estrogen and breast
01:39:26.240cancer. But let's just say, let's take an extreme case, right, which is she is actively
01:39:30.620undergoing treatment for breast cancer, in which case if it's estrogen sensitive, you clearly
01:39:34.060wouldn't give her estrogen. But outside of an extreme situation like that, do you consider
01:39:38.440estrogen and then by extension progesterone if needed to oppose it sort of mainstays of
01:39:44.140maintenance therapy for women in either prevention or even the treatment of disease?
01:39:49.260Yeah, I mean, I think those, you know, in patients where there's no contraindication, we do recommend estrogen.
01:39:58.640Another thing that really works, Peter, for women like this for menopause-related cognitive impairment is just targeted brain exercises.
01:40:05.980You 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.
01:40:17.800But let's say I restrict my right hand, I put it in a sling.
01:40:22.660I'm sorry, I restrict my left hand, I put it in a string,
01:40:25.180and all of a sudden I don't have my healthy left hand to help.
01:40:29.760All of a sudden, 10 years later, your right hand starts to move.
01:40:33.380That's the whole concept behind constraint-induced movement therapy for stroke.
01:40:39.780And I find that the same can happen in menopausal women.
01:40:43.740So 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.0.64
01:40:58.800There 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 as once a week, forcing them to use those areas, they recover function quite dramatically.
01:41:18.620You can also, in such women, use drugs like cholinesterase inhibitors because the underlying mechanism of cognitive impairment is ultimately loss of acylcholine in the nucleus basalis and areas of the brain in these perimenopausal women.
01:41:35.900And so those drugs can work. We actually, years and years ago, did a double-blind placebo-controlled trial of donapazole versus placebo in women going through menopause with cognitive impairment and found a trend in 21 patients, 21 on drug, 21 on placebo, for improvement in cognitive function in the donapazole group.
01:41:59.560So I think those, and then brain stimulation,
01:43:26.800she was in her fifties. So went from being completely normal to, uh, you know, couch ridden1.00
01:43:33.760effectively due to brain fog and just inability to do anything. And she came to me with the1.00
01:43:40.060suspicion that I think this is due to the loss of hormones. I think this is due to the, the hormone
01:43:45.860withdrawal. And, you know, after many, many discussions, not only with her, but with some
01:43:51.680other physicians, we decided to take the risk and put her back on her hormones. And the recovery was
01:44:00.980remarkable. I mean, it wasn't subtle, right? So it was very quick that she regained her cognitive
01:44:06.360faculties. And so what the takeaway for me was both the physiology, but also the choice, which
01:44:13.520is for some people, and I would probably put myself in that situation, I'd rather deal with
01:44:20.280the risk of cancer than cognitive decline. But again, the bigger question is it should be a
01:44:27.080choice. And I also have a little bit of an issue with how aggressively aromatase inhibitors are
01:44:34.420used for things like DCIS, which I think is, I don't think patients fully understand just how
01:44:43.020small the risk is that they're mitigating with an aromatase inhibitor for five years in the context
01:44:48.760of a precancerous lesion. And so I think there are these edge cases where we're doing a lot of harm
01:44:54.880without a very clear benefit. I can't agree more. And I totally, I can't tell you, I mean,
01:45:02.720patients that I've worked with who are also being seen by folks at Sloan Kettering, for example,
01:45:08.540in New York, and have decided with me, to your point about choice, that they would rather risk
01:45:15.620the possibility of recurring cancer than risk the ongoing ineptitude and inability to function in
01:45:25.740their lives. And, you know, again, I saw a young girl, this can happen, you know, the lack of
01:45:32.680estrogen driving brain fog, a 21-year-old girl that I see for migraines who's in college,
01:45:39.680and she spoke to me earlier this week and she said for the last six months she's been in a
01:45:45.800complete fog, complete brain fog. She can't function. She's in a good university. And
01:45:51.520I had her go see her gynecologist. You know, she hasn't had her period. And so the estrogen level
01:46:00.920for her came back at 22, you know, picograms per decet. It's very low. As you know, menopausal
01:46:08.200women, it's less than 30 or 35. So hers was extraordinarily low. And we don't really know1.00
01:46:14.400why that is. And was her FSH or LH elevated as significant? They were not. So it was very
01:46:19.880interesting. Her FSH and LH were normal, but it was almost like primary ovarian failure of some
01:46:25.480sort, you know. But in the meantime, she's not able to function. She cannot work at school.
01:46:32.500And 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.
01:46:48.160And 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?
01:47:02.500Yeah, I mean, I actually prefer transdermal in either a gel or a patch because, yeah, you have lower risk in my, for me, the big consideration is lower risk of strokes and venous clots.
01:47:18.360So 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 dementias 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?
01:47:45.680I never thought that patients with Alzheimer's could get better.
01:47:50.220And you really believe that that is the case?
01:51:56.440I mean, we see this over and over again.
01:51:58.060I know you and I have spoken about Obacetrapib and the profound impact it's having, at least in a pilot study when you look at the biomarkers.
01:52:05.580But the impact is most profound, the more severe your risk is. So the four fours actually have reversal. The three fours have a dramatic blunting.
01:52:17.780So, 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.0.99
01:52:38.980Because 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.
01:53:00.360We hit everybody with the exact same hammer and we blunt all of the potential responses.
01:53:06.340Now, 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.
01:53:20.980So 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, you know, it's are you triple negative? Are you ER positive? Are you HER2 new positive or negative? Those are completely different diseases for all intents and purposes.
01:53:44.340So 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.