Alzheimer Disease treatment and research has been advancing quickly recently and Dr. Erik Musiek provides and update and where we stand in diagnosing and treating Alzheimer Disease.
Without further ado, Doctor Eric Musiak completed his medical degree at Vanderbilt University in Nashville, Tennessee, and did his neurology residency at the University of Pennsylvania in Philadelphia. He then came to Saint Louis, Missouri to do his fellowship in Alzheimer's disease research at Washu School of Medicine and is currently professor of neurology at Barnes Jewish Hospital with the Washoe Physicians. Doctor Music specializes in cognitive disorders, Alzheimer's disease, neurodegeneration, and sees patients at the Central West End location. So, thank you so much for being with us today and talking with us about Alzheimer's. We're happy to be here. Can you hear me and everything? I sure can. All right, great. All right, so. You know, there's, uh, I work at the memory disorders, uh, memory diagnostic Center, I guess it's called, uh, the MDC, um, I sometimes forget what it actually stands for, but our, our memory clinic at Watch U, uh, which is a pretty large memory clinic, uh, one of the bigger ones in the country, probably, and we have At least 8 or 9 physicians now and several nurse practitioners and physician's assistants working with us, trying to expand our, our capacity um because there's been a lot going on in this field, uh, over the past few years and things are changing pretty rapidly in terms of how we treat Alzheimer's disease. So, Alzheimer's disease has always been You know, a disease that we have not had a lot to offer for. Um, it's obviously a very tough disease. It's the most common cause of dementia in people over the age of 65, and it affects almost 7 million Americans. Uh, so it's a very common disease, but it has not been one that we've had a lot of success treating. Uh, and now I think things are changing. We're starting to turn the corner on that a bit. Um, the diagnostic aspects have changed dramatically, and actually we have really good diagnostics now. We can tell people if they have Alzheimer's disease. Before they even know they have it, um, pretty accurately. And we do that in clinic all the time. And now we're starting to get a treatment uh piece in place as well. So we have two FDA approved disease modifying drugs that, while not perfect, seem to be, you know, a step in the right direction and are slowing down the course of the disease in the right patients. So I'm gonna talk today a little bit about what are the newest diagnostics that we have, uh, as well as, you know, these therapies. Uh, how can, uh, patients or physicians and other providers in our system sort of get patients to be seen in our clinic and, and what kind of patients should they be sending and, and what can we do for them, uh, if anything. So, the first thing I wanted to talk about was just sort of an Uh, uh, an overall idea of the different biomarker changes and how we think the pathology of Alzheimer's disease, uh, happens. So, Alzheimer's disease is defined by the presence of these amyloid plaques in the brain. So, these are conglomerations of this protein called amyloid beta, which is produced in our brain all the time, um, uh, and it can aggregate fairly easily in the extracellular space and form these plaques. And so if you don't have plaques, you don't have Alzheimer's disease. So I think that's an important point because some people say, oh well, I have a patient. I don't think they have Alzheimer's, but, or I think they have You know, they, they, they may have Alzheimer's disease, but they don't have amyloid. That's not the case. So, you know, you can have dementia without amyloid plaques, but you can't have Alzheimer's without amyloid plaques. It's sort of the defining pathologic characteristic. Uh, and then the other pathology we see are these neurofibrillary tangles in the brain. These are neurons that are full of this hypers. All right. I'll just keep going. Um, yeah, so, you know, just to kind of keep going, sorry about that. Um, You know, there's amyloid plaques in the brain. They're made from this amyloid beta protein, uh, which has been a big focus of the, you know, a lot of research for years, and tau, which is also a big focus of research. Um, and in general, the cascade sort of looks like this. You know, in this graph, this line is where people start to sort of show up to the doctor. This is where they're either coming to you or to me and saying, hey, there's something wrong with my memory or their family saying that, you know, where they have this mild cognitive impairment, they're starting to become symptomatic right here. You can see maybe 15 or 20 years prior to that, when they're still perfectly normal cognitively, they're getting amyloid plaque. So this is showing amyloid plaque going up. Um, so they've got plaques in their brain for at least a decade prior to the onset of actual symptoms. As you get closer to the onset of symptoms, you start to see uh tau aggregation in the brain and that kind of continues into the dementia phase. Uh, and this is where you're starting to see the brain really starting to deteriorate and see a lot of loss of neurons. Now, this is a kind of a gross thing. It's a little bit different in different people, but one thing that's pretty consistent is the amyloid is there years before the symptoms. And so it gives us this nice Decade period of time where we can actually identify people. We do this in research now all the time. We can identify people that have amyloid plaques in their brain that don't have any symptoms and then, you know, it gives us a great opportunity in the future to potentially kind of stave off this disease. Um, and there are ongoing trials to do just that to give drugs during this pre-symptomatic time, um, to prevent people from ever getting dementia. Unfortunately, we're seeing people more in this range. Sometimes over here, you know, when they're already pretty demented, um, they're already symptomatic, and we don't like deal with these people yet. Uh, so, you know, if patients come in, they, they say, hey, I wanna know if I have amyloid plaques in my brain. If they don't have any symptoms, then we generally tell them no. So we, we are not like treating people pre-symptomatically or really doing pre-symptomatic testing yet, um, particularly with biomarker tests that I'm gonna talk about. Now we actually think the amyloid plaque somehow trigger this tau pathology, and the tau pathology seems to be more uh responsible for a lot of the neuronal loss and neurodegeneration. So, you can imagine, you know, now we have these biomarker tests where we can look at markers of amyloid and tau in living people, and we can see them, and anyone that's showing up that has symptoms, if they have Alzheimer's disease, they should have amyloid plaques at that point because the the plaque should have already been there for years. And so, you know, we want to identify people as early as possible in the symptomatic period. So this is where we want to get people. Right as they're hitting that line, you know. We don't wanna get them over here where they're like, oh, my mom had Alzheimer's disease. I'm perfectly fine, 52 year old, you know, there's nothing we can do for those people. But if they're saying, hey, my memory is starting to slip a little bit, just a touch, I wanna get checked out, you know, those are the kind of people we're really looking for. And these are the people for which these new, new therapies really seem to help. Well, the further you get this direction, the less they help. Now they may help over here, but we haven't, we don't have that data yet. And in general, the amyloid biomarkers like stay positive throughout. So as I said, they should be positive for any patient that's coming in with MCI or mild, mild dementia. So, as far as the diagnostic component goes, there's a clinical component to it, and now there's a biomarker component to it. So the clinical component, um, you know, we have the luxury in our clinic of having a solid hour to spend with these people to do both a, a detailed interview with their family, so they have to bring a collateral source with them and it's very important to have this, you know, to get a really good analysis cause people are not good judges of their own memory. Um, people often don't notice when they're having these symptoms, but their families often notice. So we always have a collateral source, and we, I spend most of my time with the collateral source, asking a lot of questions about all these different domains, you know, of function. Um, and then we also use some standardized tools. So while I'm talking to the collateral source, The patient will go in the other room with a, a um psychometrician and do a bunch of standard tests like the mini mental or the MOCA. We do something called logical memory where they have to memorize the story. Short blessed test, they have to remember is John Brown, 42 Market Street, Chicago. Wordless recall is just remembering a list of 10 words. Uh, and then there's some other things, there's some verbal memory tests, there's some executive function, but most of it is focused on short-term memory because that is the Kind of most classic symptom of early Alzheimer's disease. So we have this structured, semi-structured interview with the patients where we try to do, uh, use this thing called the clinical dementia rating, which is really a research tool. I wouldn't expect anyone outside of a specialty memory clinic to use this because it takes way too long, it's too detailed, but it looks at all these different domains like memory orientation, judgment, problem solving, community affairs, home and hobbies, and personal care, and then it scores people on these things. And I bring this up because in some of the clinical trial data I'm gonna talk about, they talk about the CDR score. So a 0 is perfectly normal. So, 0 means there's no changes in any of these things. A 0.5 is sort of like the MCI mild cognitive impairment stage, where people have mild symptoms, um, that they're, they're aware of and their family is aware of. They're usually demonstrable on some some of these tests, but maybe not all. They can have pretty normal test scores sometimes. Um, but there are changes that are pretty consistent and they're there more often than not, and they, they're observable by other people. But, you know, they, they can still probably work in some cases, or at least, you know, or drive or, uh, you know, function at home in a pretty normal way. They're just more forgetful forgetting things, uh, in a consistent manner, maybe need some assistance with more complex tasks. And then these people that are, uh, in the CDR one, this is sort of mild dementia. These, these people, it's pretty clear there's something wrong. Like everyone agrees that there's a problem with their memory. Uh, and usually you can tell if you talk to them for a few minutes, they'll repeat themselves or they'll be confused about something. So they're, they're a little more obviously impaired, but they can generally stay home by themselves. Sometimes they can still drive to and from the store, you know, they can do basic skills at home. They can cook a simple meal or put away dishes, things like that. They may need some prompting to bathe, but they can do it themselves. These are the kind of patients that we're dealing with the most. People that are over in this, you know, 2 and 3, I mean, 3 people are basically like bed bound, 2 are people that are severely impaired and basically need constant supervision. So, you know, our clinic really focuses on identifying these people in this 0.5 phase where, you know, where it's hard to tell sometimes if it's just normal aging, you know, or is there some, is there really a problem, you know, and, and so if they're saying, hey, I couldn't remember the name of a celebrity a few days ago, and then it popped in my head later, that's not really worrisome. But it's like, hey, I've, you know, missed 3 or 4 appointments and I used to be able to, you know, do my taxes myself and now I can't figure out how to do it anymore and I'm an accountant or something like that. And, you know, that's more concerning. So this clinical component, you know, just so you all have an idea of the sort of patients, you know, if it's a person doesn't have to be that impaired, you know, to be referred to our clinic. In fact, I have some patients who still work at like high-powered jobs and own companies and things like that, but You know, if both them and their family is, you know, convinced that there's some sort of problem, uh, it's probably merits a referral, particularly because we're we're trying to catch people as early as possible now. Um, but, you know, it's sort of like one of those things they say, you know, if you're a surgeon, you never operate on a healthy appendix, and you're not doing enough surgeries. It's kind of the same sort of thing. We're gonna get some patients who we don't think have any problems, and that's fine. You know, it's, I'm, I'm always happy in my clinic to have one or two people mixed in and I say, hey, your memory is fine. These are just like typical problems, not, not concerning for dementia. I'd rather have that than miss people and then come in too late. And then the other component are these biomarkers. Now, these have been around for a while, but they are now much more clinically available than they used to be. So, uh, and there's really three different types. There's amyloid PET scans, which is a, there's a picture of one here. It's essentially a, a, a molecule that binds to amyloid plaques in the brain and it's a PET ligand, it's F18 now. Gives off signal if there's amyloid in the brain. It works really well. Uh, excuse me. So amyloid pet, kind of the gold standard, it's using all the clinical trials now. It used to be that we wanted to get this, but we couldn't get it because it was too expensive, it wasn't covered by insurance, but now, in the past two years, it's now covered by Medicare. So we can get it. And Medicare pays 80% and, you know, uh, it, it's worked quite well. Like a lot of our patients are getting amyloid PET. We can get them done pretty readily at, at either at BJH or at MobAC. There's PET, PET scanners there that do these scans all the time. So this is something that can be done. Our radiologists know how to deal with it. It's become standard practice in our clinic. You know, the only downside to it is the limit, you know, you can't get it at like Progress West or somewhere else. It's like only at these two hospitals right now. So amyloid pet has really become our workhorse. Prior to that, um, we use CSF a lot. So we would do a lumbar puncture in the spinal fluid, you can look at phosphorylated tau 181 and the A beta 42 ratio, which is a pretty well validated. There's hundreds of, you know, studies showing that this works. Basically indicates you have amyloid plaques, that this ratio is abnormal. And so, this has been covered by insurance for a long time. When we can't get an amyloid pet, it's the younger patient who doesn't have Medicare or something will often get CSF, or if there's other studies we want to look for. We're not sure it's Alzheimer's, it might be CJD or maybe they have an autoimmune syndrome or something, so we can send other things with the spinal fluid. Uh, so that's the nice thing about this is you can send uh other tests on the spinal fluid as well. The downside is obviously, you have to do a lumbar puncture. Now, we have a clinic at our, at our office, uh, you know, to do this. So once every couple of weeks, we have, actually we have a, a physician's assistant who's very good at it, that can do this. Um, but it's still invasive. Every now and then there's post-LP headaches, blood patches that, and, and the results are more complicated. So, if you're not used to this kind of stuff and you order CSF, Interpreting the results is a little more complicated because there's multiple proteins and ratios and things like that that are not always entirely straightforward. Whereas amyloid pets like positive or negative, pretty easy to tell. And then the new thing that's really the hot topic right now in the media and everywhere else are these plasma biomarkers. So I have to say WasU is really like one of the world leaders on this. Some of the people here, Randy Bateman, um, Suzanne Schindler are like world experts on this. And in fact, This company C2N Diagnostics has probably the leading plasma biomarker test in the world called Presivity 82. It's based right here in Saint Louis. Uh, WashU faculty, Randy Bateman and Dave Holtzman own this company and run this company, so, uh, we actually have access to this test, which it looks at this new molecule called PTA 217. It works really well, very promising. And there's studies showing that it's essentially the same as, as the spinal fluid testing. So at this point, the drug, these plasma biomarkers, which is just a blood test, nice and easy to do, they're not fully FDA approved and they're not available by for insurance payment yet. Uh, so it's an out of pocket cost. Uh, C2N has been pretty generous. We can often get these done for a few $100 and patients that have that money. Um, but my guess is in the next couple of years, maybe the next year, even sooner, you know, this is gonna take over cause these tests are just, they're getting so good that they're basically just as good as these other ones and much more easier to use. So I have to say, I, I, I would be remiss if I didn't mention this important word of warning. Amyloid pathology is really common in older people. I, I showed you that graph just last slide that, you know, people get this pathology in their brain years before or decades before they get any symptoms. So it turns out if you just took a 70 year old off the street, any 70-year-old off the street with no memory concerns, about 20-25% of them have positive amyloid pathology, have a, have a positive amyloid scan or positive biomarkers. And when you get to age 85, it's like 40 to 50%, depending on what study you look at. So, the pre-test probability in an 85 year old who has some sort of memory problems of this test being positive is extremely high. And I think this is why we don't get these tests yet on just anybody off the street, is because we don't exactly know what that means. You know, if a person comes in that doesn't have a memory problem and they have a positive amyloid test. The data would suggest that they're on their way towards getting Alzheimer's disease, but it could be 10 years, they could die of something else before then. We don't know that every single person goes on to get Alzheimer's disease that has a positive biomarker test. So, so we generally only test people who are symptomatic, and it doesn't preclude the existence of other neurodegenerative pathology. So I had a patient that had Creutzfeldt-Jakob disease, and we did a spinal tap to 1433, and they had, they had amyloid, you know, it wasn't what was causing their problems. The person died six months later, and it wasn't from Alzheimer's disease, which was at CJD. So, you know, if 30% of the population has a positive amyloid scan or a positive amyloid test, Those same people that have Parkinson's or Lewy body or whatever else can also have amyloid at the same time. So you have to really, you know, combine the clinical components and say, does this person's clinical story look like Alzheimer's with the biomarkers? You can't just do biomarkers kind of by themselves. And I think this is one of the concerns people have about plasma biomarkers becoming really widely used, is that they'll be sort of misused. So here's just a graph. Uh, this is from Suzanne Schindler's paper. I forgot to cite it, but it's uh in, in, um, Alzheimer's and dementia, just coming out now. Essentially, this is the C2N PTA 217 a beta 42 plasma test. Uh, this is a receiver operator curve against amyloid PET. You can see this blue line here, like it's really good. Like it's almost just as good as amyloid PET at detecting uh uh pathology. So, These plasma biomarkers are gonna be here very soon. I'm sure we'll be talking about them a lot in the next few years. They're gonna make their way from the neurologist's office into the primary care office really quickly. My guess is they're gonna become part of some sort of like age-related standard workup that people get, you know, and, but we, we're not quite there yet. So therapy. So I'm gonna spend the rest of the time talking about these therapies and uh what they're like, and then they're somewhat controversial, I guess. I mean, they, I, I don't know why because they seem to work reasonably well, but there are, you know, there's controversies that all address about side effects and that, you know, is the, is the, the juice worth the squeeze, so to speak. So, The first one of these that came out was this drug called Lacanumab or Lakembi, which is now available. We've treated over 300 patients with Lakembi already at our place. Um, what is it? It's an anti-amyloid antibody. So it's a monoclonal antibody which targets aggregated forms of amyloid. And when you give it to people, it, it triggers microglia, monocytes to remove amyloid plaques from the brain and they actually go away. And so it's given every 2 weeks by intravenous infusion. And then there's a lot of stuff that can happen with it. I'm gonna go into more detail with the patients need MRI's every, you know, every so often during the first year, um, because of some of these side effects. The main one called ARIA, and I'll talk about a lot. Uh, you know, it's a very involved drug at this point. So, you know, we'll talk about the data and how good it is, but it's a drug that's not for everybody, for sure. Um, it's only for people that have very mild symptoms, and it's only for people who kind of have the ability to come in every 2 weeks to get an infusion, and get MRI's and be very reliable about that kind of stuff. Uh, it's also expensive, so you probably, it's covered by Medicare, but, uh, there's some out of pocket expenses, uh, uh, associated with it. So, In 2022, uh, this paper came out, and we were kind of watching this for years before that where lecanumab was actually the second, uh, I'm not gonna talk about aducanumab, which was the very first antibody that was approved by the FDA cause it kind of, uh, failed in, in actual clinical use. It never really met the endpoints in the, in the in the uh phase three trial. It was very controversial. I could spend the whole hour talking about that, but I'm not going to cause we don't use it. Uh, this is the second antibody. It's called litanumab. It's probably better than aducanumab. Um, it's made by Biogen and AI. And in the, in the phase three clinical trial, they had about 1600, 1700 people. All of them with mild cognitive impairment or mild Alzheimer's disease, based on the clinical dementia rating. So they all had a CDR of 0.5 or 1. So these milder kind of people, and they all had to have a mini mental status score greater than 21, so out of 30. So 21 is not great, to be honest, like this is probably too low. Um, I'll get into that later, but, but these are the people that were included. So you, you know, it's still mildly impaired on this test, mild to moderate impairment on this test. And they had to be amyloid PET positive. So they have to have plaques because the drug removes plaques. So they're treated every 2 weeks for 18 months. Um, and you can see here's a graph of the amyloid PET. So the people that didn't get any drug have a lot of amyloid in their brain and it's reduced essentially to almost negatively, you know, you can't detect it anymore in some of the patients. So it does remove, takes it about 18 months, but by the end of 18 months, the plaques are gone. And if you look in the, in the, in the trial, they looked at a lot of different functional and cognitive endpoints, but the one I'm gonna talk about is the clinical dementia ratings of boxes, which is just like the, the clinical dementia rating that I was talking about, which is not a cognitive test. It's a functional test. It's basically how well is this person doing in those five different domains of function. And you can see that there is separation between the group. Everybody gets worse, so it doesn't fix you, it doesn't cure the disease, it doesn't turn back the clock. Um, but the people on thecanumab get about 30% less. They, they, they get worse at a 27% slower rate. Uh, over the 1st 18 months. Now one thing is important to remember, it takes almost that whole time to remove the plaques. So it's, I think, fairly impressive that there's any signal here because it, you know, you're basically removing the plaques, you know, you're not probably gonna see an effect so you've removed a decent amount of plaque. And so even with this short compressed time frame. Um, they still met the primary endpoint. Everything was, you know, they met multiple endpoints, all the secondary endpoints on this. So this was a very successful phase 3 trial. Now we'll talk about whether or not this 27% on this test is enough to legitimize these drugs or not. So this was FDA approved July of 2023, we've been treating people with it since August of 2023. And I said, over 300 people so far, and, and it's gone pretty smoothly. Uh, but the major concern with these drugs, um, aside from, are they effective enough, is this thing called ARIA or amyloid-related imaging abnormality. So it turns out that people that get amyloid in their brain, they get plaques in the parenchyma of the brain, but they also, some of them get cerebral amyloid angiopathy or CAA so they get amyloid in the blood vessels as well. This happens even in people that aren't treated with these antibodies. And the telltale sign of that is they get these microhemorrhages. You see these little black dots on MRI? They have to have a special kind of sequence, either a GRE or SWI sequence to see these. Um, but it turns out that this drug, because it's stimulating the immune system to remove amyloid, and there's a lot of amyloid moving around, a lot of inflammation, it can worsen this. So it can actually cause these microhemorrhages in the brain. They call it AIAH for hemorrhage. Uh, part and parcel to that, sometimes when you have this inflammatory response, you also get some edema in the brain. So this would be really severe AEAE or edema. You can see the edema kind of throughout this whole hemisphere. This is really bad. People always show like the worst case they've ever seen. A more typical case of REAE is this. So, you know, this is kind of what we see more often. It's just kind of a little area where there's some Flare hyperintensity on, on the MRI usually asymptomatic. So, if you look at the numbers from the Clannumab study, you know, the, it's complicated going through these numbers. I don't wanna go through every single number, but You know, the point is, You know, the percentage is symptomatic RAE is only about 2.8% of patients, so. About 20% of people get some changes on their MRI, um, but only about 2.8% are symptomatic. Uh, and I think that holds in our experience. Most people, we just see something on the MRI and then we say, hey, we have to change your dosing cause you're getting some Maria. Uh, we've had a few patients that have had headache, and there, there's a bunch of symptoms you can have with it. Headache, dizziness, confusion. They're sort of nondescript, um. And a few people that we've had to, you know, treat them with steroids or admit them for the into the hospital for a few days, but it's been very few, probably less than 2.8% in real life. The biggest problem people are people that have APOE4. So you probably know uh APOE is this gene that's really important for, it's the biggest risk factor for sporadic Alzheimer's disease. And if you have the E4, uh variants, you have a higher risk of Alzheimer's disease by about 3 to 4-fold. If you have two copies of it, then you have about a almost a 20-fold increase in risk for Alzheimer's disease. So these people, they're only about 2 to 3% of the general population, these E4 homozygotes, they have a lot more ARIA. About 9% of them are symptomatic, and almost 30% of them um have ARIA E. So, The E4 homozygotes are a little bit higher risk group. Everyone has some risk, you know, but the E4 homozygotes we keep a very close eye on, in some cases, if they have other risk factors, we won't treat them. Some centers don't treat them at all, so we have to test everybody for APOE genotype before we start them on these drugs. So I think I I'm spending a lot of time on AA because it's it's a huge issue. I don't want to downplay these symptoms. They, they, you know, there are a few people, about 4 or 5 people that have died, um, on these drugs from hemorrhage in their brain, or from really severe RAE out of about 7000 they've been treated. So it can happen, it's rare. Um, most of the cases are really manageable, even if we see AEA, you just stop the drug and it usually goes away within a few weeks. You can even restart the drug in many cases. Um, and that's why we get these MRI's every now and then. But you have to take this seriously. It's the kind of thing you need proper infrastructure to monitor these patients. Um, but in the grand scheme of, of side effects, yeah, these are, these are scary, but they're not that scary. I mean, I think it's a relatively safe, uh, drug. So, a big argument against these drugs is that they, you know, then it's not a big enough clinical effect to really be valuable. Um, so I wanted to address that a little bit, and I think that There's some people that are kind of on on the internet and whatnot, kind of portraying this in a way they don't think is exactly accurate. So if you look at the placebo group, this, this clinical dementia rating, it's been used in hundreds of clinical trials, and then generally, people drop about 1 point per year on an 18 point scale. So you go from 0 is perfectly normal, 18 is like dead basically. I mean you can't do anything. No, most people don't get to 18 because they die before that. I've never seen a person who's an 18 on this clinical dementia rating scale. Uh, but it's theoretically possible if you got 3 in every single category. So people go down by about 1 point a year. And so the people on the leanumab, they. Went down about 0.5 point over the course of a year of a year and a half, there was about a 0.5 point difference between the two groups. So, you know, that's a 20%, 27% difference, you know, it's about a third. Um, But what we don't know is how is that gonna play out over time. So if you look at the whole clinical dementia rating scale, 0 to 18, you know, the mild range is up to about 9, and then beyond that, things go downhill quite a bit. So, if you just drew these lines out like I've done, we're basically here. This is the data we have. It's really at the beginning. The two lines are just starting to diverge. And if you follow that out, you can see that it could take several years longer to get into this moderate range, you know, in, in, in this group, the placebo groups getting there at about 9 years and, you know, this group's getting there about 14. So I mean it could have a significant impact if these graphs hold up. We don't really know if they're going to. Uh, it's possible, you know, in a, in a best case scenario, that maybe it looks like this. Maybe over time, it's even better, and these people never go down to like a, you know, CDR uh some of boxes of 9 or 10. They just kind of even out and they're they have mild dementia and it just stays that way. I doubt that'll be the case, but it's possible. We don't have data to know. But what some of the people who are critics of this drug are suggesting is this scenario in which this is all the benefit you're gonna get, the 2% argument. They're saying half a point on this scale out of 18 is only 2%. Well, that's true if they never had any further uh benefits. So these, if there's basically separation here and then the two lines stay parallel the rest of the time and you never get any more than this 0.5 a point, then yeah, this drug would not be worthwhile at all. But there's no reason to think this is gonna be the case. I mean, there's no data to suggest that this would happen. It doesn't even look. Really feasible when you look at the graph. So, I think it's a bit of a misinterpretation of the data to say, oh, there's only a 2% effect. There's a 27% effect because it would be impossible for someone to have more than 1.5% improvement in 18 months because they, the placebo group only dropped 1.5 points or 1.6 points. So the best you could possibly get would be a 1.6% improvement if the drug was perfect and there was no, no decline. And 1.6 points is only what, 7% or something on this scale. So, beware of that argument. I mean, I'm hoping this happens, it'll probably be something more like this. The data so so far looks like this. And in fact, so here's the data we have. Uh, this is uh withanumab. The problem is, here's the 18 month mark. This is where the trial ends. And, and since the drug was approved, everybody got the opportunity to go on drugs. So there is no more placebo group. So we don't know, you know, we can't really look anymore because there's no placebo group. Everybody's on the drug, it's an open label extension. But what they did, what, what uh AI did, and you can take it or leave it, um, they compared to this thing called ADNI, which is a historical control. So it's a huge study that's followed hundreds and hundreds of people with Alzheimer's disease longitudinally over time, and they have a lot of data on clinical dementia rating, and basically the, the purple line, it, it superimposes pretty perfectly with placebo groove that we saw. And then they just extended that out over 36 months, and compared to the historical controls, at the 36 month point, you're seeing about a 1 point improvement in the clinical dementia rating scale, which is about what you'd expect, you know, it was 0.5 at 18 months, at 36 months, it's 1. So it looks as though those two lines are kind of keeping the same trajectory, um, but we'll have to see. Over time. And then there's this argument about, is this enough, you know, is this enough of an effect. To legitimize the use of these drugs. And so, one of my colleagues, Sarah Hartz, uh, here at WashU has done this analysis of all the data from the lecanumab trial and she basically looked at how many months it would take you to convert from, from kind of mild to moderate dementia. And it really depends on how early you were caught, you know, how early did we start the drug. So people with a really low baseline clinical dementia rating of like 1, they gain about 16 months. Uh, in their ADLs, IADLs. So these are things like driving and, you know, cooking a meal and stuff, more complex stuff. They gain about 16 months before they lose the ability to do those things, more than they would have had. Uh, for the basic ADLs, these are like bathing and eating and things like that. It's about 28 months, so. You know, you can decide if you, if it were me, if I can like gain another 28 months of being able to bathe and myself and dress myself, it's probably worth it. Um, but, you know, It's different for every patient. You really have to kind of weigh all the factors with each patient. So, we don't kind of push patients into it cause that's the last thing we want. It's a, it's a pretty big undertaking. But I think to say that there's no benefit of these drugs is it it's inaccurate. I mean, there is a benefit, it's just, you know, it's not a cure. So there's a second drug now that's been approved called Dananimab or Casula. Uh, it's from Eli Lilly. It is a, it's also an anti-amyloid antibody. It targets a different moiety on the amyloid um called pyroglutamate. It doesn't really matter. It also removes plaques, it removes them faster than lecanumab. Their phase trial was almost identical to the lecanumab phase trial. Uh, they did one other thing where they did tau PET imaging to look to see how much tau people had in their brain, but that's just sort of like an academic point. The key points about denanimab is is once a month instead of every 2 weeks, which is a big difference, a big improvement. Uh, and then their model is that, so with lecanumab, you just keep treating them forever, I guess. Uh, after 18 months, they have the option of switching to a once a month maintenance dose that goes on after that. But with danimab, once the tau pet is negative, or once the amyloid pet's negative, the plaques are gone, you can just stop the drug. In fact, that's how it's intended to be. So this is appealing to people to say, hey, it's only once a month, and after 18 months I'm done, you know. So we'll see if that ends up being as good as, as staying on the drug. I think that's still an unanswered question. But in the clinical trial, Dananumab looks great. It looks, you know, just as good if not better than lecanumab. Here's some of the data. You know, danimab, it can remove the plaques. This is amyloid pet, seeing the plaques are removed really you know, faster than with licanumab. They saw a 36% slowing in their clinical dementia rating scale, and um it depends on which population they look at. The higher risk people have a little bit worse effect and the lower risk people have better cognition when they start, have less of an effect, a better effect. But in general, somewhere about 3, you know. And to me, that's reassuring that both these drugs have a similar mechanism of action, and they both have very similar, like degrees of efficacy in these, in these trials. So, and in their phase two trials, they kind of look the same. So it seems like that's kind of what you're gonna get out of removing amyloid plaques at this rate, is you're gonna get about a 30% slowing of the 1st 18 months. So this was actually approved in July of 2024. Uh, we have about 50 patients on it now, you know, we Uh, patients like the idea of it, probably better because it's once a month, um. It has a little bit higher ARIA rate potentially, so. You know, you're seeing. Trying to point out the important points here. It certainly in APE4 homozygo, it's almost 40% of them developed of some kind, which is a lot. Uh, and for the, you know, some of them are severe. So, That's high, a little bit higher than Lecanumab, um. You know, depending on what kind of AIA, we can break it all down in all different ways. In general, the nimab had a little bit higher rates, you know, somewhere in the, you know, about 20% for the APE4 non-carriers and almost 50% of all, all kinds of AIA, but this is ARIA H, I'm sorry, and people with uh APE4 homozygotes. So, At this point in our practice, people who are E4 homozygotes, we kind of steer clear of this drug at this point until we have some more data because we just, it looks like it's a little bit, you know, 50% R rate is starting to make me uncomfortable to some degree. Um, so we kind of stick with aanumab and the kind of the higher risk patients. Um, but for your average patient who's not an E4 homozygo, uh, Dananimab is a, is a pretty good option, uh, for the most part. And the clinical usefulness, Sarah Hart's also analyzed. It's very similar toanumab. It might be a little bit better. You know, people that have mild symptoms, they may gain 21 months of uh additional um independent ADLs and 37 months of the basic ADLs, you know, if you start them really early. So, this also shows like if you're starting people later. You know, people that are on at the low end of the, you know, a little too demented probably to be getting these drugs, it doesn't really help them very much. And their risk of, of side effects is just as high if not higher. So, you know, when I talk to patients, I try to explain that, you know, there's, there's a lot of patients who are maybe just a little too progressed for the, for these drugs. I'll say, hey, I, I could give you the drug, but it's not gonna help you and it's gonna put you at risk. That risk-benefit ratio is really not in your favor. So, Um, that's the way that we sort of think about it, even though that's a tough discussion for sure. Uh, this is some interesting data suggesting these people that are really mild. So people that had a mini mental of, of 27 or better. Um, so, a normal mini mental score, but they had a positive amyloid PET scan, the CDR 0.5. They had like a 60% slowing on this IADRS scale when they got to nanimab. Uh, and a 46% on the clinical dementia rating. So, it looks like it works better as I, you know, Sarah Hartz's data would suggest too, the earlier you start it, the better it works. You know, 60%, you know, is something you can get behind. I think a little bit more maybe than, than 27. So, you know, this is exciting. There's trials going on right now where they're treating people who have no symptoms at all, have perfectly normal test scores, but have positive amyloid scores, uh scans. So, Those are very difficult trials to do. They take a long time. Um, there's always risk involved, uh, but we'll see if that works. I'm not sure it's a great long-term solution because these drugs are really expensive and have side effects. We might need better drugs, but that's where we're headed with all this, with the blood tests and the pre-symptomatic, uh, diagnosis and treatment. But we don't do it now. So what are the differences? I talked about this a lot, you know, they're pretty similar drugs. Dananimab's big advantage is that it's once a month and it has a stopping point. Um, safety-wise, lecanumab looks maybe slightly safer, although it's hard to compare the two trials. There's a few little differences in the, in the population. The danimab population is a little higher risk. So we'll we'll have to see how it plays out. You know, we're keeping a lot of data and comparing. So far denanimab seems pretty similar to lecanumab in in the real world. So the near future, um, what's gonna happen with these drugs? Where are we going? Leanumab, anytime now, probably this summer will be coming out with an at-home subcutaneous uh injection. Which would be a game changer cause then you don't need the infusion center anymore. It's gonna make life a lot easier for people to be on that drug. So I think then they may jump ahead again because suddenly it's like, I don't have to get infusions. I can just do this infusion, this injection at home for, you know, patients that can manage that. You know, we need to figure out a lot of things. When do we stop these therapies? When do we do maintenance? You know, do we restart them again if people start to decline again? Um, how do we figure out who's gonna get ARIA and who's not, you know, how do we figure out who's gonna respond better than others? So all this data, there's a million research questions just waiting to be answered here. Um, And what, what do we combine this with? I think this is a first step, but we're probably gonna be combining these with other drugs that can augment their ability to, you know, prevent different aspects of pathology. How's that gonna look? So that's the next 10 years of, of this. The other near future is there's a 2nd generation of these drugs coming, which is way better. And actually I'm really excited about it. And you know, these are in trials now. But some of these new drugs, the problem with these drugs is they don't cross the blood brain barrier well, so only about 1 in 1000 molecules actually gets into the brain. But they have these new versions now. Roche has one and AI has one that are attached to this molecule that is binds to the transferrin receptor. And so the transvern receptor can shuttle things into the brain across the blood-brain barrier. They call this brain shuttle. Um, and so like 7 or 8% of the antibody instead of 0.1% gets into the brain. And the initial trials with these new drugs, it looks like you can clear plaques almost 100% of the plaque within a few weeks. And the ARIA risk seems to be much lower. Now, we'll have to see if that pans out in the phase 3 trials, but the phase 2 trials looked unbelievable. So, and they were just showing that in a meeting um about 2 months ago. So, you know, like I said, the first step forward, I wouldn't be surprised 5 years from now if we're using drugs that are a whole lot better, uh, and, and getting a lot better effects. Um, so who do we treat? You know, I've gotten over this a little bit, um, You know, these people have to be, we're basically using the clinical trials as our guide right now cause that's all the data we have. So, you know, mild MCI, mild AD, mini mental, greater than 22, for the most part. It's not a hard cut off, but that's what we like to see. CDR 0.5, so mild symptoms. They have to have positive biomarkers, so they have to have plaques. They have to have an MRI within 12 months of starting the drug, and it has to less than 4 microhemorrhages, uh, cause if you have too much CAA at baseline, you can get bleeding in your brain when you take these drugs. Having microhemorrhages at baseline is the biggest risk for future ARIA if you take these drugs. No superficial cirrhosis cause that can indicate bleeding in the brain, you know, no acute strokes or tumors in the brain, other things like that. You have to be able to get MRI's too. So we have this issue, people that have bad claustrophobia or they have some sort of, you know, implant or something and they can't get MRI's or, you know, defibrillator that's not, you know, able to be MRI, then, then that's a no go for those people. Cause you can't, you have to get the MRIs, it's not safe otherwise. Obviously, if you're in bad physical shape and have other medical problems, you probably can't get this. That's sort of a, you know, the active cancer one's tough. People that have kind of slow, indolent sort of cancers and things may still be options. Um, and then AE4, for homozygotes, uh, you know, those are people that we have a long risk benefit conversation with, depends on some of their other risk factors. You're APE44 positive and you've got 4 microhemorrhages and you're on anticoagulation, I'm not doing it, but Um, you know, if you're otherwise healthy, then it might be something, a risk you're willing to take. Uh, anticoagulation, uh, is a theoretical increased risk of hemorrhage that I mentioned a couple of people have died on these drugs and they were almost all on anticoagulation or had gotten TPA or something cause they had a stroke. Uh, so there is some risk, although in the Clarity AD trial, they treated people on anticoagulation, there's no increased risk uh of ARIA with those patients. So this is, I think, a pretty modest risk. You know, this is what we got right now. These criteria are gonna be changing over time. A lot of people are ineligible for these criteria actually. So, it's kind of a small segment of people that actually need all this. About 25% of the people that we see in our clinic probably qualify for this. So that means Of the whole greater world of people with dementia, it's a pretty small percentage. You know, this is our treatment algorithm. We're sort of thinking if they, if they look like they have Alzheimer's disease and they don't have any other signs of other neurodegenerative diseases, then we have to get all these tests, you know, we look for all these contraindications and then we say, are they candidates or not. If not, then we sort of, we still see them and treat them as best we can, but they might not go down this amyloid therapy route. Um, Yeah, so I'm gonna skip through this a little bit fast, you know, this will sort of just give you an idea, so. You know, if someone out there has a patient that they think, huh, this person seems to have memory problems and they're still pretty mild, functioning pretty well. Let's send them to NBC. We see them. You know, we spend an hour with them. We do clinical dementia rating, we do all the testing. We say, right, yes, they seem to have what, what looks clinically like they meet all the clinical criteria, uh, then we get the biomarkers. Uh, we discuss all this at the first visit. Actually, I start talking about biomarkers and these, these therapies uh with appropriate patients at the first visit. You know, we make sure they've had a brain MRI. We use our own protocol, um, that has to have all the right uh imaging sequences, and then we get blood work, you know, B12, thyroid tests, CBC or CMP. Once all that's done, then the biomarker testing, usually we just send people for amyloid pet, that's the easiest thing, but there are these other options. Um, if they're positive, and then they're heading on this road towards potentially getting these therapies, then we get APOE genotyping. That's kind of not an interesting story. It's not covered by insurance, so I usually have people do, there's an online at home thing you can do, uh, costs 100 bucks to get your AOE genotype. I often just have send that to patients and they do it at home. Um, You know, and so then once we have all the data, then we have a discussion with them, we have a special clinic set up. It's called the anti uh amyloid Immunotherapy clinic AIC. They go there, they have a big conversation. Um, if, if they're going down that road, then we have, you know, people in the office that can kind of do all the legwork to, to make this happen and then And then they start up. So, this is sort of this algorithm we've created for our anti-amyloid immunotherapy clinic. Uh, we have two terrific, uh, nurse practitioners and a great uh physician's assistant that just do this and they're really expert at it. So, you know, the Sometimes, the general neurologist or the primary care doctor does all this stuff, you know, and then they can, there, there is a pathway being developed where they can go straight into the AIC if they've done all this stuff. So some of our general neurology colleagues have been working with us to sort of, you know, get this all sorted out so that they can do all this themselves and kind of skip the line for MDC. Otherwise, it's a complex case so they don't want to do all this stuff, which I completely understand. They can refer to the MDC. We see the patient, do the whole workup and then put them into the pipeline, um, for everything else. And then once they are referred to the AIC, uh, the MPs there just take care of everything in terms of getting them set up, all the infusions scheduled, the MRIs, the insurance, etc. etc. So. It's become a reasonably well-oiled machine over the past year. And I'll just kind of finish up, um, you know, like I said, we had about 300 people. And it's going pretty well. We have a paper coming out very soon. Uh, you know, this is sort of what it looks like though. The number of people being infused is just going up and up and up. So it's taxing the BJC infusion infrastructure and the MRI machines for sure, but, um, you know, we'll probably reach a steady state at some point, particularly causedanimab requires less infusions, uh, it has a limited lifespan, so we'll see if that helps, or this at home infusion injection version. Um, so, you know, so far we, uh, the rates of Ao that we're seeing in real life are a little bit better than what the clinical trial said, and we haven't had any really scary, uh, side effects. I'm gonna skip this the, the, the challenges are obvious, you know, like you have to have accessibility to our clinic. You have to be getting MRI's, you have to be able to kind of understand all this. You gotta come in and get infusions. Um, it's hard to know if the drug's working, you know, that's the other thing, uh, you know, and differentiating AIA, you know, the symptoms of AIA, headache, dizziness, confusion, they're very common. These are people with dementia, they're older. Uh, sometimes it's hard to know like, oh, do I need to get an MRI on this person or not? Uh, and that's sort of a judgment call. Luckily, we have a 24 hour call schedule now where there's someone on call that can take care of these patients anytime if they are on these drugs, uh, to help make that call. Um, You know, I mentioned some of these there there's a lot of A lot of still questions to answer. It's very early days, and we are early adopters for this, so there's not, no one to look to except ourselves for answers usually. So, I'll take a minute and just go through a clinical case just see have some ideas. 76 year old woman, and, you know, retired realtor, educated, some kind of typical medical problems, has had depression for a long time, two prior hospitalizations. She's been on a bunch of meds, and right now she's on Lexapro and Wellbutrin. Um. You know, her husband's noticed decline in her memory, uh, for the past 2 years, let's say, she has trouble concentrating, easily distracted, loses her train of thought. Um, she's made some mistakes, uh, with doing things like her medications. She's having difficulty like cooking a more complex meal, following a recipe, some word finding difficulties. Seems to be unable to kind of finish a sentence without pausing. But otherwise, she can still drive, she can still go out with her friends. She bathes and everything on her own. She can do basic stuff around the house without any problems. You know, she's, in terms of memory repeating within a few hours sometimes asking several times, hey, what time did you say we were going to that thing? Um, can keep her on calendar, but she has to write things down right away or she forgets it. You know, she can drive, she might have trouble going to an unfamiliar area, might get a little confused. You know, complex problem solving is a little worse. She like turns to her husband for more help. has trouble managing complex situations. And you know, it's a little harder for her to pay the bills, cook a complex meal, leaving out an ingredient now and then. She used to be a fantastic cook, but she can shop and drive and things. You know, still volunteers at the local museum, but she might not lead a tour on her own, cause she might forget something, no issues with personal care, no other symptoms to suggest that she has a different neurologic disease. Um, and the depression has not been great. It's been worse over the past 6 months. She's feeling anonic, guilty, no suicidality. She feels like her meds are not helping. So, she gets her test done and they're kind of borderline, 25 out of 30, and they mean mental, some verbal fluency problems. Only remembers 3 out of 10 words from a list. We like to see 5 or 6, you know, mild impairment on remembering a story. So it's sort of borderline, uh, not terrible scores, but not perfect, you know, so this is a person that would be a clinical dementia rating of 0.5. Um, because she is, there's evidence that there's some sort of problem with her cognition, but it's pretty mild still. And the question is, is this Alzheimer's disease or degenerative disease or this pseudo-dementia due to her poorly controlled depression? And so, you know, we treat the depression, but now, you know, we can also look at amyloid in their brain and see use biomarkers. So we started on Janepazo, got a brain MRI. Uh, not too exciting, pretty normal looking brain MRIs. Tests were all normal, blood work, etc. So, she got an amyloid PET and amyloid pet was positive. You can see around the edges of the brain, there's bright signal that suggests there's uh amyloid in the cortex. And so, you know, she had AEGN type of 334. So we diagnosed her with Alzheimer's disease. This was not pseudo dementia. Now, her depression may be making it worse, but she has underlying Um, Alzheimer's disease. So we referred her to to psychiatry to work on her depression and to anti-amyloid therapy clinic. So this is the kind of patient where the, the biomarkers really make a huge difference in differentiating. In years past, we would have waited around for years to see if her, you know, how things go, and it would have been too late for her at that point, so. Um, so the take home points, biomarker based on AD diagnostics, they're here, they're ready to go. Refer your patients, we can do them, uh, but we only treat people who have symptoms, and we only test people to have symptoms, not just because they are afraid. Um, amyloid immunotherapy is readily available. We're doing it now. 300 patients, um, so far, so good. It has a modest effect on disease progression, and we don't know the long-term benefits, um, and it's only really effective in early stage disease, so we got to catch people early, but new drugs and better drugs are, are right around the corner. And then for people that are interested in this, there's this agile MD pathway and Epic that BJC is creating that's gonna help you like order all these tests and things and order the right MRI and the right PET scan and all that, and that's coming soon, but at this point, referral to our clinic is the easiest option. That's it. Thank you so much. OK, there are, let's see, the first question was, Would you recommend all patients with MCI have an amyloid PET or other biomarker test, or only those meeting other criteria such as family history of Alzheimer's? No, I think anybody, the family history, you know, we see plenty of people who have no family history that have amyloid, you know, that are the first. So, the family history is not that reliable. People, you know, grandma died of hardening of the arteries or something. We don't really know what happened, you know. So I would say anybody that sort of meets the clinical criteria that seems to have MCI. Yeah, it's worth getting it checked out for sure if they can, you know. Uh, unless they, uh, you know, what would be more of a disqualifying factor is if it's, well, they have MCI, but they have Parkinsonism and they're hallucinating a bunch of other stuff, or they had a big stroke or some other disease process, but if there's no other like obvious culprit. Yeah, I think regardless of their family history or other factors. You know, it's worthwhile. OK. And then there was another one. For those of us PCPs in the rural Missouri with limited access to anti-amyloid therapy, would you please give us your thoughts on the appropriateness of use of, OK, Drazole? Oh, sure, yeah. So I didn't talk at all about depazole, but I, I use it all the time. So all the patients that I refer to the AIC are already on Depazole. So, Um, I think that or riva stigmine, any of the acetylcholine esterase inhibitors, they work pretty well, actually, they. You can't tell they're working. They don't cure the disease, but at least for the first few years of disease, I think it's definitely worth starting that, you know, that's something you can kind of do. Um, certainly, you know, this is one of the huge issues with these drugs. They're really only available in like cities that have a big academic medical center. They're, they're not even available in big cities that don't have, you know, major academic centers. So availability is hugely problematic. There's whole parts of Saint Louis where we have zero patients that have ever, you know, like North Saint Louis, and there's like 3 patients that have gotten these drugs, like it's crazy. So. Um, it's very tough if you don't live like right near here to kind of get this, uh, you know, the availability is a problem. Um, certainly, we have some people that drive long distances. Um, the infusions can be done outside Saint Louis, so there are more and more infusion centers that are doing the infusions. So if you get your diagnostics done here and then you go to Sullivan or someplace else, you can probably get You know, infusions done there or close to there. So that makes it a little bit easier, but it's still a, a big problem. But, but putting people on tonerazole and even mementine um is, is certainly something you can do without all this stuff. OK, and then she also asked, in addition to that, do you continue these meds along with anti-amyloid therapy? Yeah, yeah, so people just stay on them. There seems to be no downside to that. And I think, right, hold up. I would love to know Doctor Muziak's thoughts about the benefit of estrogen or testosterone therapy, aiding and cognitive decline and neurogenerative disease. Yeah, I'm not really an expert on that, but it is an interesting question. So we certainly see um there are cognitive effects of menopause, you know, when, when your hormonal changes occur. And we don't know as much in men, but certainly men have lower testosterone with age as well. So, Uh, the data, uh, I, we don't generally recommend people like get hormone replacement because of memory loss, um, but I would say the data is sort of mixed on that. So, uh, there are some patients who seem to have, particularly, uh, women that go into menopause that can have like pretty acute memory changes afterwards and sometimes that improves with hormone replacement. So, I'm not really an expert in that area. It's not something we like recommend people do, but I'm not saying, you know, it may help some patients. And testosterone, I have no idea. I have no idea if that helps or not. OK, thanks. How easy is the pet approved when ordered by primary care? Do you recommend a specific diagnosis to use? Yeah, so you can use mild cognitive impairment, that one seems to, or Alzheimer's disease, either one. I don't know the answer to that. I mean, I, I have to say that I'm somewhat isolated from that. I ordered the test and we have some people, if it doesn't get approved that kind of like take care of it for us. So I don't really know. Um, and I, I don't know if the insurance companies are looking to say, all right, this person's a memory specialist, like we'll, we'll accept their amyloid PET scan. So, Um, might just have to order one and see, but yeah, mild cognitive impairment is probably the best uh diagnosis to use. I think we also, you know, our data, our, our notes, we have this full hour with the patient and a whole psychometric battery. So they're full of data. So it's harder for the insurance company to push back because whatever they ask for, we've probably done, you know, they've, they've had a whole bunch of cognitive testing, they have a bunch of test scores, they've had MRI, they've had all these other blood work done. So, uh, it's harder to reject cause there's just fewer holes in it, I guess. So, uh, you might just have to find out.
