Anti-Amyloid Updates with Dr. Mia Yang

Welcome to Ask Dr. Mia Answers on Dementia Caregiving. I am your pocket geriatrician and memory specialist. When I was helping my mom with her cancer journey, I knew I wanted to be her advocate and her care partner, but I didn't expect to have to rehash old patterns of communication like a teenager. Combining my knowledge as a specialist for older adults and my own experience as a sandwich generation care partner, I am here to empower you to take practical steps to not only care for the older adult in your life, but also take good care of yourself. Welcome. Welcome back to Ask Dr. Mia. Today I am talking about an update on anti-amyloid therapy. These are the new drugs that we have out in the market for the past couple of years that are able to remove the amyloid protein in the brain as a disease-modifying treatment for Alzheimer's disease. I have previously talked about these drugs in prior episodes, but that has been almost a year ago, and I wanted to let you know some frequently asked questions that I hear in my clinic from patients and their families about these drugs. And by no means this represents a patient-physician relationship, and the information I am sharing today are purely for educational purposes. But I think because there is so much information out there, it is potentially helpful to you to hear from me as a memory specialist who has treated hundreds of patients who are potentially being evaluated for these medications. So one of the questions that I just wanted to set the stage before we get specifically to the drugs themselves is just about how the what we used to call Alzheimer's disease or Alzheimer's dementia is not what we call Alzheimer's disease today. Whenever I mention the word Alzheimer's, most people automatically unfortunately think about people who are living in memory care in a nursing home, who are quite impaired in their daily activities and have already lost a lot of their daily independence. That is a moderate to severe form of dementia. And in the past, the diagnosis of Alzheimer's disease was reached from excluding other potential causes. So, for example, ruling out the presence of strokes, other medications, other conditions such as sleep apnea, depression, uh hearing impairment that may be contributing to one's hearing memory loss, and what is left over when we could not find another reason is oftentimes labeled as Alzheimer's disease. But what the symptoms people have that may look similar on the outside actually probably had different things happening in their brains on the inside. And this is a reason why potentially a number of uh clinical trials failed when uh they were only testing on people who had similar symptoms but different biology. Uh in the development and the research for Alzheimer's disease causes, amyloid protein is now needed for the definition of Alzheimer's disease. When Dr. Alzheimer's first diagnosed and labeled a woman with Alzheimer's disease, it was based on what they saw under the microscope in her brain after she passed away. And that was the presence of amyloid plaques as well as tau tangles, T A U tangles. And the presence of amyloid plaques and tau tangles really are the pathophysiologic definition, meaning what is actually happening inside people's brain under the microscope that now defines Alzheimer's disease. And prior to the past couple of years, we really did not have any biomarkers, uh, imaging scans, or blood tests that could identify Alzheimer's disease. And you may hear on the news that Alzheimer's could develop for years or even a decade before symptoms onset. They're actually talking about the presence of amyloid protein as a defining feature of Alzheimer's disease. However, Alzheimer's disease and related dementias are actually oftentimes overlapping in terms of the proteins that are happening in the brain. And pure, uh where you only have the presence of amyloid and tau, Alzheimer's disease is actually quite rare. We think that it is only about 20, less than 20% of the time, people only have amyloid and tau and no other conditions. The most common overlapping condition is with vascular disease or vascular dementia. But you can also have other conditions like Lewy body, where the presence of alpha synonuclein or frontal temporal dementia, the presence of tau. And this is another common clarification in that dementia means that there is a loss of independence, usually in the mild form, are things related to managing finances, medications, driving. And in a more moderate stage, is when people are having impairment in their personal grooming. But the word dementia is an umbrella term that contains multiple different diseases, where Alzheimer's dementia is the most common one. So in terms of uh these uh medications, we really have two primarily. Uh, one is called Lacanamab or Lakembi, and the other one is called Donanimab or consula. And we know that people who are being evaluated for these medications sometimes have the choice between the two. So, what could be the differences between them? Usually only people who have a uh mild dementia or what's called mild cognitive impairment are eligible for these medications. So if you score too poorly on memory tests or have impairments that are really more uh needing reminders for bathing or dressing, you're you most likely not candidates for these medications. And just as we said that Alzheimer's disease and related dementias are oftentimes overlapping conditions, uh, part of what a memory specialist needs to do is to be able to differentiate how much is the presence of amyloid protein or Alzheimer's disease likely to be the cause of what you're experiencing in terms of memory loss and not something else like vascular disease or uh a Lewy body and other conditions. So, how do doctors now confirm whether someone has Alzheimer's disease? A number of tests need to be ordered. One, there needs to be uh confirmed memory loss, usually on some sort of memory testing. Preferably it's compared with other people of your similar age or education, or what are called neuropsychologic tests. Um, there also needs to be a brain MRI, um, usually really to look for underlying small vessel disease that may make someone not a candidate for these medications. Of course, there needs to be some sort of confirmation of amyloid presence in the brain. Most doctors are starting with a blood test. Um, you may have heard that the FDA has approved of several different blood tests for the detecting the presence of amyloid protein in the brain, and they all have fairly good um sensitivity in terms of corresponding with what we see on brain scans. So, for example, one of the most common ones and the um probably the best one is what is called P tau 217. Uh P stands for phosphorylated Tau, TAU-217. And even though uh it is measuring and labeled as phosphorylated TAU, it is much more sensitive to the presence of amyloid protein, but that is a common confusion. When that blood test is abnormal, it can be because of other chronic conditions like chronic kidney disease. If you don't have chronic kidney disease, most likely that test is probably accurate. However, I would say that probably the standard of care is to confirm that blood test with an amyloid PET scan or a lumbar puncture. So the lumbar puncture would sample the fluid in the spinal fluid that is draining out of, you know, inserting a needle into the low back, or an amyloid PET scan is a nuclear test that uh injects a tracer that binds to the amyloid protein in the brain, makes it light up if you have them, and then that is read on a CT scan. It is similar to the PET scans that are used in cancer to look for cancer cells, but this is specifically for the presence of amyloid. And then the final test that is usually ordered is another blood test, but this one is to look for a gene called ApoE gene. And this is a gene that we all have two copies of. People may have different variations of E2, E3, or E4. Um, what you can remember is that E4 is really uh one of concern. E2 is likely protective against the development of Alzheimer's disease, E3 is neutral, and E4 increases one's risk of developing Alzheimer's disease and also increases their risk of having side effects on either Lacanimab or Denanimab, Lacambi or Consula. And typically the age dur uh cutoff uh for these medications is a little nuanced, but there probably is a general criteria between 50 and 85. When people get to above 85, there tends to be potentially the presence of another condition called late. It's an abbreviation, L-A-T-E, that looks similar to Alzheimer's disease, but does not necessarily actually have the presence of amyloid. And that is usually very, very slow progressing, where people may even pass away before they develop significant impairments from late. These medications do not cure Alzheimer's disease. Even the folks who take these medicines do have some decline in their memory. However, the compared to people who are getting the placebo or not taking these infusions, people have slower decline on their memory testing and function. These medications will not make your memory better either. And there is probably a nuanced discussion about how much benefit one could realistically expect. When I talk to my patients one-on-one, I tell people that on an individual level, if you start these medications, it's hard to know what, how, how slow or how fast your actual memory would decline because you don't know and I don't know the path not taken. When people are compared as a group among those who started Lacanomab or Denanimab versus placebo or compared to observational cohorts of people who are not on these treatments, what we do know is that there is a slowing down of the disease over time. Now, how much slowing down does that mean? There are all kinds of numbers out there, but I would say that after a year and a half of treatments, the difference between the two groups is modest at best. So if both groups started with a B minus on their memory test, uh a year and a half later, both groups still have some decline to a C, but there were probably a little bit more people in the treated group that remained at a B minus or C rather than deteriorated to a D or an F. When you look and talk with pharmaceutical representatives, uh that data could be as high as 87% of people who are on Lacanomab are able to remain at, say, a B minus rather than further declining. Between the two medications, probably denanomab or consula has a faster clearance of amyloid protein, but when you look at the data showing the difference in terms of memory testing, um that they were probably fairly similar. Um, it's questionable whether denanomab potentially has a bigger difference, but that's highly debatable. Um, and that uh the goal of these medications is to slow progression, which may help preserve function and independence for people who are really at that border of being independent, fully independent for themselves, versus needing some help with things like driving, managing their medications, managing their finances, which to many of my patients is a very, very important goal and that many people would do a lot to try to preserve their independence because they're still at a mild uh disease state to benefit from these medications. So when we are specifically looking at these two medications, I wanted to share a um uh a slide that really shows how the medications differ in terms of slight differences in terms of slowing the progression. On the left side, if you're watching this video, is for Lacanomab. On the right side is for DanaMab. And these are published studies that uh you can find and look if you choose to. And uh it's showing that in the light blue line is the treated group, and then the darker purple line on the left side is the not treated group. The Canomab also compared the treated group with what's called a delay start, meaning the people who were originally randomized to placebo after the 18-month of trial, they were allowed to get the real drug or during the open label extension. And you can tell as the lines differ that the difference between the treated and the untreated group actually grows over time, and that the delayed treated group actually never quite catch up to the group that got treated first. Um, and then Lacanemab also compared those who were treated with what's called an ADNI cohort, A DNI. This is a well-known uh observational cohort where people are just monitored over time, they're not given medication, so serving as a control group, you can see that the difference in the scoring of the memory tests got bigger from half a point approximately to about one point. And on the right side, you see similar changes for denanomab as well. Uh the nanomab did not compare those who were treated first with those who were treated later. They just compared it to the ADNI cohort. The red line is the treated group, and then the blue line is the adne group. And the difference at a year and a half is about a 0.7, so maybe a little bit more than 0.45 for Lacanimab, but at 36 months or three-year mark, the difference actually grows where it's a difference of 1.3 versus a difference is of 0.95 for Lacanimab. The details of the numbers probably don't matter as much as the point that I want to make, which is why that these medications are disease modifying, meaning in the beginning, the difference between the two groups are relatively small, but these two lines actually start to diverge and become farther from each other as time goes on, and that those who are treated hopefully remain relatively stable, uh, but those who are not treated have uh more decline over time. Now, um, what are some potential side effects? And the main side effects that people worry about are what's called aria, A-R-I-A, and it's an abbreviation that stands for amyloid-related imaging abnormalities. And there could be two types. One is called ARIA-E, standing for edema or swelling, and one is called ARIA H, uh, standing for hemorrhage. So, as you can see in the MRI scans of the brain on this particular uh slide, you can see that the swelling look like white areas. And this is really the brain having an over-response in terms of inflammatory response. What these medications do is that they bind to the amyloid protein, generates an immune response, and it's the our body's immune response that removes the amyloid protein. And this is also a reason why uh if you are on strong immunosuppressants for rheumatologic or inflammatory bowel conditions, it's questionable whether you would actually uh benefit from these medications if your immune system is severely suppressed, where you're not able to mount an immune response, you may not benefit because your body is we need a body's response to be able to remove the amyloid protein. Uh aria H or hemorrhage, these are tiny, um tiny little dots that look like a drop of blood in the brain. And um thankfully, we're we're not talking about major bleeds, but that is the fear and the concern in that uh people could have, and a handful of people have died from these medications, especially when they were also given a very strong blood thinner in the treatment for, say, a heart attack and ischemic stroke, where there's a blood clot that goes and blocks a blood vessel in the brain, uh, or that they had to get a blood thinner because of blood clot in the leg. In the lung. So all of those are potentially fatal conditions where if you have a very high likelihood of having a heart attack and you're diagnosed with, say, Alzheimer's disease and are under treatment potentially for these medications, that could be a dangerous combination because doctors would have a hard time giving you blood thinner, not to say that it never will be given, but there may be a delay to make sure that there is no bleeding in the brain, because giving a blood thinner and you being on these medications can be a deadly combination. The people who have the highest risk for having aria or swelling or bleeding in the brain are people who carry that APOE4 gene. If you have no copy of E4, great, fantastic, you're at the lowest risk. If you carry one copy of E4, you're at intermediate higher risk. And then if you have two copies of APOE4, you're at unfortunately the highest risk, whereas some institutions around the country will actually refuse to give you these medications because of the higher risk of bleeding. Some uh institutions, including our own, will not give it to you if you're on a blood thinner to treat atrial fibrillation like Eloquis or Pixaban. These medications can increase the risk of bleeding in the brain. And so different institutions around the country could have slightly different criteria depending on where you're getting treated. And the baseline MRI of the brain is very important to really get a good detailed look to make sure that people don't have tiny droplets of microhemorrhage or tiny droplets of blood. Tiny droplets of blood can occur in people who have uncontrolled high blood pressure, or they can also occur in a separate but related condition called cerebral amyloid angiopathy, where the amyloid protein is not deposited in the brain tissue itself, but in the brain vessel wall. So when you're starting to remove amyloid, uh that can make the blood vessels more fragile and more likely to bleed. Unfortunately, people who have two copies of the E4 gene also have a higher risk of having that amyloid removal cause weakening of the blood vessels in the brain and little droplets of blood coming out. Almost looks like a little tattoo of a dot in the brain because the iron in the blood never gets cleared out, even though the body clears the blood itself. Most of the time, aria tends to happen in the first six months of treatment, where if you make it through the beginning, most likely the risk significantly reduces, which is also why we scan people's brain so often in the first six months. Typically for uh either Donanimab or Lacanomab, you're getting almost a monthly MRI brain for the first three months, and then you get another one at around the six months mark. If you have either one or two copies of the April E4 gene, then you get another MRI brain at around the 12-month mark to really look for aria, either the swelling or the bleeding. Now people ask, you know, what could those symptoms mean besides what's showing up on the brain? And the symptoms for a thankfully is not very common. So most of the time we identify aria just based on what is picked up on these monitoring MRIs. But people could have a bad headache, confusion, vision changes, uh, dizziness, trouble walking, and of course, if it's serious, people could have seizures and have symptoms that are suggestive of a stroke. So if you are someone who has chronic headaches and you start these medications, it can be hard to figure out is this a headache that's due to you know not getting a good night of sleep, or is this a headache due to these medications? And so knowing that people who have, say, for example, chronic headaches may get additional MRIs, or people who already have dizziness and other uh gait changes may get additional MRIs on top of the monitoring MRIs is something to consider. And when you look at the clinical trials, the actual uh published rates of ARIA edema and hemorrhage are um are listed anywhere from around 13 to 17 percent uh for both in total uh in terms of Lacanomab, very few are symptomatic, about 3%. For denanimab, the original trial had much higher risk of ARIA, um, but uh we no one really uses the original uh titration doses of denaminomab or consula that's published because there has been an additional study showing that if you modify the dosing of Donanimab to start low and go slow and gradually increase, then you reduce the risk of ARIA significantly to about the same rate of between 13 to 20 percent. Um, obviously a higher risk in those who are Apo E4 carriers and around 3 ish percent, uh, maybe a little bit less, uh, that are symptomatic. And this is pretty consistent with what we're seeing in the real world as well. Very few people have severe aria, less than 1%. And um, in our practice, it's really someone who had worsening confusion was found to have a lot of swelling uh on the brain, on their routine MRI that just happened to be around the time that the confusion happened and had to be hospitalized, treated with IV steroids, thankfully improved, and the drug was discontinued. Um so most of what we otherwise see are more mild aria where people may not have even had symptoms and are then you know having a very you know detailed discussion about the risk and benefits of continuing uh treatment uh depending on how severe the aria is. So this gets complicated really fast uh in terms of you know how many little droplets of blood are there, what kind of symptoms there are. So having a uh health system that is equipped to rapidly scan people's brain in terms of MRIs, communication with emergency departments. This is another reason why it's generally not recommended for people to say do international travel when they first start these medications because of the risk of potentially needing to go to an emergency room, um, and you don't want to be in another country and not being able to get in touch with your regular physicians. So um, so the issue of blood thinners really can be um depending on where you go and where you get infused, some institutions will allow you to get them and get either Lacanimab or denanomab while other people other institutions will not. So, how are these medications given? Uh Lacanomab uh initially started out as every two weeks IV infusions, uh, but that has recently changed. I'll talk about that in just a second. Denanomab is usually every four weeks infusion, meaning you go to an infusion center, the nurses check you in, they check your vitals, they start an IV, they give you the medication and monitor you afterwards. The whole time may take two-ish hours longer if you have any symptoms that they're monitoring you for. Um, and it's, you know, it's it's it's work. Um uh and it's something that takes not only your time, but someone who can go with you in terms of a family or friend to make sure that if you do develop any allergic symptoms or other unexpected symptoms, that you're safe to uh you're not, we're not depending on you to drive yourself home. Uh in very mild symptom uh symptomatic patients, they may be able to drive themselves to and from uh their infusion center, but usually uh just to make sure that everything is okay and no unexpected symptoms and allergic reactions, typically infusion centers require that you have someone go with you. Like going to the colonoscopy. You can't get the colonoscopy if you don't have someone drive you home. You can't get Lacanomab or DanaMab, at least not in the beginning, unless you have someone who's with you and can drive you home. Uh, more recently, at the time of this recording, which is the middle of September in 2026, uh, back in July of 2026, the FDA actually approved of Lacanomab uh bypassing the infusions every two weeks for a year and a half to these injections, or what's called ICLIC injections that can be done at home on a weekly basis. These injections look very similar to other existing injections. For example, you know, for Manjaro or other GLP1s, uh, other biologics that people might be taking, where typically they're mailed to you from a specialty pharmacy on ice. You put it in the refrigerator and you take it out whenever you need to inject yourself. For Lacanamab, this IClick or self-injection has really opened up more convenience for people who don't want to necessarily go to an infusion center, and we're all still working on making sure that people are still monitored and safe in the very beginning as they inject themselves. For Lacanimab, this is actually two doses of two injections given at the same time every week for a year and a half. After that, Lacanemab does have a maintenance dose, and that has to do with how Lacanimab works. It targets both the mature and the immature form of the amyloid protein. And the thought is that even after you remove all the mature form, your body is still producing immature forms of the amyloid protein. And so uh even prior to July of this year, there was already a maintenance dose of Lacanem that can be given after a year and a half or 18 months of treatment. Um, but that maintenance dose is just one injection every week instead of the treatment dose of two injections every week. Not confusing at all. Um but uh I think the pendulum has swung back and forth, and it's good that the drug companies ESI and Lily are competing with each other in terms of Lacanomab and Dananamab, respectively. Uh when Lacanimab first came out, it was only Lacanomab. And then when Donanamab came out, uh more people wanted Donanamab because it was more convenient. Once a month infusion rather than twice a month infusions. But now with Lacanomab coming out with the injectable, more people are interested in Lacanimab again. So I think this is really exciting in that there are um other uh drugs that remove amyloid even faster with less side effects in the pipeline, as well as other targets for Alzheimer's disease that's not amyloid in the pipeline. So all of this is really very, very uh exciting, and there's definitely potential for newer therapies to be FDA approved in the next year or so, uh, which makes a lot of people potentially want to do Lacanomab or DanaMab now uh with the potential of switching to something newer or better down the line. So um one question that I also sometimes get is you know, can I travel? And I would say typically local travel is okay, you know, within continental US. Um, but if you are traveling internationally, uh, we would typically, and and different people may have different preferences, but uh typically we really recommend to avoid international travel for at least the first six months of treatment because that's when the aria are most likely to occur, and that we want to make sure you're getting the necessary medical care that's on an emergent basis in a reliable manner. So, what should caregivers monitor for? So typically we ask people who know the person living with Alzheimer's disease to, of course, pay attention to their memory, their function, any new neurologic symptoms, headaches, uh falls, uh confusion, or new behavioral changes. And all of those can be discussed with the prescribing uh providers, um, depending on what the situation is, to try to suss out is this something that is related to the infusions or the drugs, uh, or is this something separate? And then people also ask, you know, does insurance cover this? Um, and I would say yes, Medicare covers most Medicare Advantage plans cover as well. Some plans make us go through a lot of rigmarole to get these approved, but typically um places will not uh schedule for the infusions unless insurance gives their blessing. Um, in terms of out-of-pocket costs, very variable, really depending on if you have a secondary insurance uh or kind of what your own plans, deductible, and co-pays are. Uh, some of the patients that I have taken care of where their insurance did not pay for very much have had a about a $500 out-of-pocket cost. Now, this is just local experience and who knows what it is for for other people. Uh, but $500 could be way too much and not affordable for some families. So that's something to consider. Um, and then the the injectable form of Lacanimab is also covered under Medicare Part D, as in dog or drug coverage, versus the infusions are covered under Medicare Part B. So there might also be differences in terms of out-of-pocket costs, really all the intricacies of American healthcare system. That's a conversation for another day. Uh, manufacturers for these medications do offer some assistance, uh, typically for people who don't have insurance, not necessarily for people who have insurance in terms of covering for very high copies. Um, and yeah, I think when it comes to which drug to choose, this is where you really have to talk with your prescribing clinician about your specific risk, your APOE test result, um, as well as what you prefer in terms of convenience and you know, whether you want a drug that sort of has a maintenance dose, uh, or you want to be done with something. Um, and so one other follow-up question that I oftentimes get is, you know, how fast does amyloid reaccumulate? Does it reaccumulate back faster or stronger or worse in some way? No, we don't think it you know comes back more intensely, but we think that amyloid plaques build up at the rate of about 2.5 centeloids. Centeloids just a unit of measurement on amyloid PET scans. Most people start at the time of diagnosis, at least for us, somewhere between 60 to 90 centeloids, and the cutoff, uh, at least for us locally, is around 24. So they're definitely um abnormal on the amyloid pet. It's a it's a separate discussion. If it's less or very just over the borderline, then we really have to think very uh hard about how much is this uh Alzheimer's disease uh versus something else causing the memory changes. But say you go from a 60 centeloid of amyloid presence on the beginning uh amyloid PET scan, and you do these one of these therapies for a year and a half. Um, potentially we could repeat the amyloid PET scan to see if you have achieved amyloid clearance. So let's say bring the amyloid scenteloid down to a five, then at the rate of 2.5 centeloids reaccumulating every year would take probably eight to ten years before it gets back to the cutoff of abnormal. And that may also play a role in terms of your other medical conditions, how long you know your other members of your family typically live, um, in terms of lifespan. And so all of those things are probably important to consider as well, um, and that uh and that this is a rapidly evolving field where new things are coming out all the time. And so uh if you're listening this farther in the future, just know that uh the this information that is shared currently may be out of date uh at a future state uh in terms of the the differences between the two medications. I hope this is helpful uh in terms of just explaining an update uh about these medications, and um this is also to uh help me uh have my patients take a listen to this in a general sense in terms of reviewing what I tell them individually in a clinical setting, because this is a lot of information to go through, and I hope that this helps clear up some of the most frequently asked questions when it comes to lacanimab and denatomab. And my and oftentimes people ask me, you know, what would I suggest if I have someone in my family uh who is uh potentially being considered for lacanimab or denatomab. And I would say that as a geriatrician, I tend to be naturally a little bit conservative in terms of medications. I'm not someone who thinks that newer is necessarily better. Um, and I think that if you're a someone who has very little other medical comorbidities, that you have confirmed presence of amyloid, you have very mild or mild disease, so mild cognitive impairment or mild dementia, um, there is another study called AHEAD that's going to come out in the near future that tells us whether it's beneficial to give these medications to folks who have no symptoms of memory change, but just a presence of amyloid protein. So that's content for another episode down the line. But if you have very little vascular risk factors, you're not taking blood thinners, you want to take something that can slow down the disease progression, then yes, I would say that these are the medications for you, uh, and that you're willing to kind of put into work to either get the infusions or the injections and have potentially someone who can go with you, especially in the beginning, just to monitor for side effects. For people who live alone, um, this can be challenging because it's hard to know exactly when symptoms of ARIA may occur. It's not that it necessarily is always going to be the same day of the infusion. Um, and this is where you know monitoring for potential symptoms, those headaches, dizziness, confusion, uh, trouble walking, rather subtle things that if someone doesn't know you well may not detect, um, that can be risky in terms of monitoring for side effects. So, with all that said, um, I hope you enjoyed this episode. And let me know uh by emailing me or contacting me on my website, Miayangmd.com, if you find any of this helpful or any other content you would like for me to cover in future episodes. If you enjoyed this episode, please also leave me a review wherever you listen to podcasts or on my website. Really appreciate that as this is another way that other people could uh find out about this podcast and share this with someone you think might find this helpful. Thank you so much. Talk to you next time. Thank you so much for listening to this episode. Please click the follow button on your favorite podcast platform. Please remember that this is educational content and that do talk to your own doctor if you have specific questions. Original music by Grant Willis. The podcast is edited by Builder Librarian. And finally, please repeat after me by taking care of myself, I can better care for the older adult in my life.