The Science of Memory, Alzheimer's and Dementia

Narrator: 0:01

Welcome to MedEvidence, where we help you navigate the truth behind medical research with unbiased evidence, proven facts powered by ENCORE Research Group and hosted by cardiologist and top medical researcher, Dr. Michael Koren.

Dr. Michael Koren: 0:16

I'm glad to be back on the stage with Dr. Steven Toenjes, my colleague, and we always have a good time when we're here, and hopefully educate people along the way. So I'm a cardiologist and Dr. Toenjes is a neurologist in expert in Alzheimer's disease. So I'm going to be sort of more of the host interviewer, maybe throwing a few concepts where neurology and cardiology actually cooperate with each other. It doesn't always happen. The more likely scenario is that we're trying to give you blood thinners that you have to deal with when they cause side effects in the brain. But here we can, I think, be on the same page and work together and help the audience understand what constitutes Alzheimer's Dementia and give them everybody an opportunity to ask the expert questions. So, without further ado, here's our first slide, so you can see the sense of humor of our staff. You usually look better in your picture, Steve.

Dr. Steven Toenjes: 1:17

Right, yeah, I guess I've gained a little weight, yeah.

Dr. Michael Koren: 1:23

All right. Well, we'll have to work on that, but in the movie version of your life story we'll have to get something that looks a little bit better than that, anyway, okay, so we always like to get the audience involved. So let's start with question number one, which I think is the only question. So it's a little bit deceptive, but if you get it right, you won't have to have another question. So here's the audience question. A positive amyloid PET scan, which stands for Positron Emission Tomography showing the buildup of abnormal amyloid protein in the brain is indicative of Alzheimer's disease. So who thinks that's true and who thinks it's false? And who's sitting on the sidelines so they don't get it wrong. Okay, that's smart. So the actual answer is a positive amyloid PET may mean a person is experiencing the early stages of Alzheimer's, but people can have amyloid plaques and never develop the symptoms of Alzheimer's. So that's already a puzzle to start.

Dr. Steven Toenjes: 2:25

That certainly is a puzzle. It's something that I think is worthwhile to at least think about or kind of address. First by a show of hands. Who's before this question that even heard of beta amyloid? So there are a few people that have actually heard of that before you know. We've come to find out since the initial description of, pathologically, what we find in Alzheimer's disease patients, that one of the first things that really seems to start occurring as much as 10 to 20 years before a person has their first symptoms with Alzheimer's disease, that an abnormally cleaved substance or protein named beta amyloid is precipitating out around the neurons of our brain. It is something that is part of what we would consider a pathologic diagnosis of Alzheimer's disease. However, it is not 100% specific. Just because there's beta amyloid present doesn't mean with 100% accuracy that the person has Alzheimer's disease. They probably do, but there are ways to have. There are false positives with beta amyloid scanning, and that is actually a very important point to understand as things like amyloid PET become increasingly available for coverage via Medicare.

Dr. Michael Koren: 4:06

And thank you for that starting point. So what we like to do in medicine is to bring this to the attention of our audience in terms that they can understand, and we do that in something called a case study. So we created this case study called mild cognitive impairment, and involves a typical person that may come to see you, Mr. Pipe Wrenchworth, a plumber. And that's you, well, the guy who looks like me in the picture. And the only thing that makes me worried about is that if that is in fact me, then I probably need some memory assessment, because this woman who's been my wife for 24 years is somebody I've never met before. So we'll have to figure that out a little bit. So my staff has a guy I think it must be my brother. He looks a lot like me, but I can tell you that I have nothing to do with this woman and she's 64 years old. Her name is appropriately Fawcett, and she brings her to your office for memory evaluation and Mr. Wrenchworth pipes to you that Fawcett has been having trouble remembering names and even when she's prompted with details she's not able to pull out that memory. But she's still able to function independently around the house. She can drive the car to run errands. So her primary care doctor tells them that that's just normal, age-appropriate memory loss. But they're not quite convinced and they want to go to the expert. So they come to her office and say what's going on here? Is this Alzheimer's? How do we assess it? What do?

Dr. Steven Toenjes: 5:49

Very common question, very common reason for a consultation in a neurology clinic. So a few things are helpful to understand. There's a lot about our bodies that change as we age, unfortunately that is true. And our brains do change as we age as well. We do have normal changes that occur with aging. Memory loss is not one of those changes. We do significantly, as an example of normal change, slow down. Our ability to shift and focus complex attention or so really slows down, and while attention type changes, slow down can start to become deficient. That can seem like a short-term memory problem, but not necessarily be a memory problem. So part of the challenge in this scenario is to try to decipher is what the person experiencing actually a memory complaint? Because, as I mentioned, memory loss is not a normal part of age-related cognitive change. If there is memory loss, there is damage, there is something wrong, whether that be vascular, whether you've had too many beers through your life, whether you've had too many traumas through your life, or whether you have a degenerative condition such as Alzheimer's. And so testing clinical cognitive testing to try to decipher what actually is the deficit that the person is experiencing, because if it is actually memory-related, as I just stated, that is not normal age-related cognitive change. With the overriding important consideration, the person's specific question is this early Alzheimer's disease. As I mentioned before, you have pathologically what is going on in Alzheimer's disease for 10 to 20 years before you ever have your first symptom. So the person could absolutely have Alzheimer's disease at this point. As a matter of fact, they may have had Alzheimer's disease pathologically for more than a decade with minimal to no symptoms.

Dr. Michael Koren: 8:15

Okay, so let's flush this out a little bit for the audience, or, in this case, let's flush it out for the audience, given the nature of our patients, pun intended. A nd so I'm gonna actually skip ahead first, because I wanted to change the order a little bit in what we do. The first thing you mentioned that I think is important is dementia has many causes, so I think it's very important for the audience to understand that when you come in for an evaluation, it could be something that's a memory issues. I had nothing to do with Alzheimer's or a former dementia. There's nothing to do with Alzheimer's, so why don't you break that down for everybody? Sure?

Dr. Steven Toenjes: 8:59

so what's listed up here, or things that are Some of our more common ideologies for cognitive decline? Certainly vascular disease. If we've got enough injury in our brain on a vascular basis so essentially stroke related injury or small vessel degenerative type changes that have been in the correct places in our brain, and the amount or sheer volume of vascular injury can certainly start to cause a cognitive decline. That one is almost Universal. It is very, very common for us to have vascular damage in our head. It's certainly by the time we're starting to get, if we're lucky enough to get to our eighth decade, and so while that happens in almost everybody as a society We've witnessed almost all of our Elderly that are reaching their eighth decade have at least some cognitive decline, and that's why our society in large considers cognitive deficits as we get older as Normal, because it happens to most people so that represents damage.

Dr. Michael Koren: 10:16

But then so the type of patient that comes to you helps you understand if it's more like to be Alzheimer's or something else. So my typical patient had a heart attack at age 60. They're having some memory issues or they don't feel as sharp as they did. More likely they have some carotid artery disease or maybe micro emboli to the brain.

Dr. Steven Toenjes: 10:36

So just a little bit about the company that things keep or or maybe they had a bypass and they spent time on a bypass machine.

Dr. Michael Koren: 10:45

Yes, that's a good point. So there is. There are some data out there that show that if you have your heart disconnected from your Circulation, there can be subtle changes in your memory. The reasons for that could be air emboli, air from the pump going up to the brain and causing some damage, or other Inflammatory issues that occur during open heart surgery. So that's one of the arguments for trying to do less invasive cardiovascular interventions. Go ahead.

Dr. Steven Toenjes: 11:13

Sure. So the vascular Contributions to to cognitive decline are very, very common. But there are people that get it to their mid 80s with absolutely no vascular disease whatsoever and as long as not there's not some other etiology For a cognitive decline as they're aging, that person's memory will be just as sharp at 85 as it is at 40. There are other degenerative conditions. Everybody in here has heard of Alzheimer's disease. Most people, if we took a show of hands, probably have not heard of Lewy body dementia. That is the second most common cause of a degenerative dementia and most people have never even heard of it. But everybody's heard of Alzheimer's disease. Obviously, Alzheimer's disease is by far the most common cause of a degenerative dementia and it is so common. Everyone's heard of it because either their family has been directly influenced by it or indirectly, by knowing someone close to the family that has been influenced by that disease. There are other degenerative diseases, l ike people with Parkinson's and a significant percentage will start to develop cognitive decline. And then the front of temporal dementias that have been a little more In the news recently, with Bruce Willis being diagnosed with a front of temporal dementia, and so while in the clinic and we're trying to decipher one. Is there actually a problem beyond normal age related changes? Is there something that we're suspicious may be degenerative, meaning slowly progressive in nature? And then, if so, is it something that would be on this list? Is it primarily memory related, ie more typical of an Alzheimer's pattern or other patterns that decipher themselves? A Lewy body dementia patient and a front of temporal progressive disorder clinically are are fairly different. They're fairly distinct.

Dr. Michael Koren: 13:21

So the person that got hit in the head a lot a boxer, for example Is that we're using to describe front of temporal lobo, or degeneration is one of the sub elements of that.

Dr. Steven Toenjes: 13:31

No, a chronic traumatic encephalopathy. You know, those people really run a much higher risk of actually developing Alzheimer's. And one of the interesting and confusing things that we've come to find out is that the pathology actually looks a lot like Alzheimer's disease, and so yeah.

Dr. Michael Koren: 13:59

So the take home message here is that there are a lot of different forms of dementia and If you're having some memory issues, you want to understand what's the driving factor and then address that. So let's go back to Alzheimer's, and there's a lot of different hypotheses of how this occurs, and this is a mind-boggling list and I don't expect you to go over everything, but maybe just give people a brief introduction of some of the ideas here.

Dr. Steven Toenjes: 14:26

Sure, so the first one is the amyloid hypothesis, and that is the hypothesis that the a majority of our funding in terms of research trying disease-modifying. F ind therapies by disease modifying, meaning therapies that alter the course of decline in a patient with Alzheimer's. And while we mentioned the beta amyloid is one of the first things that starts to precipitate. It's been thought for a long time that if we could impact that, that altering the precipitation of beta amyloid within our brains, it may, you know, alter the course, and so that's what we mean by amyloid hypothesis. We'll talk more about that later. There are other pathologic precipitants. The number two there lists, tau protein. Hyperphosphorylated tau protein is a different substance from beta amyloid. It starts to precipitate in a cascade of things that are thought to be triggered by beta amyloid deposition. First, tau, hyperphosphorylated tau protein deposits actually within the neurons of our brain and seems to kick off a process that tells the neurons of our brain to just start dying. In everything around the therapeutics and the research and all of these hypotheses center around how does that beta amyloid initially deposit? How does that process then end in tau deposition? How does tau deposition then end in triggering death of the neurons in our brain, and certainly inflammation is a part of the story. If we jump down to number seven, just general inflammatory stimulation does seem to accelerate the process that occurs that ends in degeneration, and so that's really what almost every single one of those is geared towards explaining.

Dr. Michael Koren: 16:51

So we all have it. And the question is, why does it fold in a strange way? In the way I like to help people understand, that is, if you have a towel, you can roll it up, you can flatten it, you can lay it out, and it's all the same material, but the way you configure it will have a very different function. So if you fold it in the wrong way and it gets in the wrong place and it causes problems, it falls to the right way, there's no problem. And it's a little bit of a mystery as to why certain things fold correctly and why they don't, and the question Is whether or not a tau has some influence on that folding pattern. A bsolutely, and it I just brings to mind for me that if you just consistently fold the towels wrong, you don't get asked to fold them anymore. Okay, there you go. Yes, and then the other thing where kind of a overlap is this lipid invasion model. It sounds really nasty, but the blood brain barrier is something that usually separates your circulation from what's going on your brain. I guess there's a theory that that can break down and then your brain becomes subject to some of the inflammatory influences of the circulation and your gut and your gut. Y eah, and one of the things that's a misconception is when people talk about circulating cholesterol, they think that's what your body needs to go about its functions, but in fact, cholesterol is so important to the cellular functions of all your tissues that every tissue of your body makes cholesterol by itself. Your brain makes cholesterol, you, your skin makes cholesterol, your bones make cholesterol, because cholesterol is needed for all these cellular functions. The stuff in your circulation is the extra stuff your body's trying to get rid of. But if this balance between the brain and the circulation breaks down, that's one of the concepts and I bring that up because we're actually doing a clinical trial right now that's looking at a drug to treat lipids, to treat cholesterol issues, that we think may have a positive impact in dementia, called Obicetrapib. So if the question's about that, I'm happy to elucidate All right. So let's move on here. We covered this and this is the pathology. I don't know if you want to.

Dr. Steven Toenjes: 19:09

These are just, sometimes a picture does justice. The darker colored is just what a pathologist would look at during an autopsy or a brain biopsy scanning for amyloid plaques. That is the dark circular substance there and then the bluer structure in the blue picture. The brown thing is a tangle that is wrapped up within a neuron that is started to degenerate and die. And that's when we take postmortem and do an autopsy on someone's brain to look for the pathological entity of Alzheimer's disease. This is what the pathologist is looking at staining for amyloid and then hyperphosphorylated tau and the pattern, which is something that can actually be done in a live individual. Now we don't take your brain out and put it back, but we started off with the amyloid PET question. We can actually do radio labeled measured densities of amyloid deposition within our subcortex and cortex. We also can do tau-based imaging. The tau PET is not really clinically available. It's largely just done in the research world. Although it is possible to do, it's just not possible to get any insurance payer to cover it. But increasingly now we are starting to be able to do amyloid PET imaging and measure the presence and density, hopefully, of beta amyloid in a live individual.

Dr. Michael Koren: 20:56

Now we can also measure for your levels of tau protein in your circulation. That's a little bit controversial.

Dr. Steven Toenjes: 21:07

No, I think within a relatively short period of time. It's difficult to predict the future, but there is a massive amount of research looking at blood-based markers that are markers for these things being present in our brain, and we do have some that are very reliable and really should roll out as approved and in use blood tests, quite literally a serum blood test for Alzheimer's disease. I think the one that will probably win and become what our society will likely use is tau 217. It is not really something easily clinically available but tau 217 in the future is very likely to be our serological way of estimating whether this stuff is in our brain and that really will come to pass.

Dr. Michael Koren: 22:04

So that's a rapidly evolving science and we've done some screenings looking for patients in the general community that may have higher levels of tau protein, and it's getting better and better. So that gets into the concept of what is hereditary and what's modifiable. So why don't you jump into that a little bit for the audience?

Dr. Steven Toenjes: 22:23

We hear often, and appropriately. So I forgot somebody's name and the other day and my mother had Alzheimer's disease and so a person becomes concerned. That's a very, very logical reason to be concerned if you've had a parent who was diagnosed or and you watched the unfolding of the course of Alzheimer's disease. Alzheimer's disease is so common. It turns out that really the inheritability of it is really not the main thing that we're really concerned about, particularly when someone's problems started after the age of 65. When mom or dad started to develop a progressive decline and they were 75, 80, 85 years old. That's really not a strongly inheritable thing, it turns out. Of course, inheritability is always at least to some degree relevant. But if we ask okay, you're concerned, you have a loved one who had the onset of their cognitive symptoms, how old were they? If you tell me in the clinic something before the age of 65, we're really going to start worrying a lot more about the inheritability of it. And certainly if you said my father developed Alzheimer's at the age of 50, that's probably an inherited condition and then inheritability of it is something we really do need to worry about. The rate being so high within individuals as we age, the inheritability of it washes out just from the sheer frequency. If you take everybody in the United States, 85 and above, that has any cognitive complaint at all, 50% of that cohort has Alzheimer's disease. So it's that common of a problem. We definitely think it is always worthwhile. Everybody in this room should think it's worthwhile to understand that. There are modifiable risk factors for Alzheimer's disease though, and a lot of the estimates are that the modifiable risk factors are things that we can really alter. Certain things like not getting repetitive head traumas that is a big risk factor. Actually Having blood pressure in midlife. So in your 40s and 50s it actually turns out to be really useful to control your blood pressure and that significantly alters the likelihood of developing Alzheimer's down the road. You see the things listed there. Of course you would try to not have a stroke and if you get diabetes, try to control it. A few things that are not that intuitive. One listed is hearing aids. It turns out that as we lose our hearing, it's actually important for us to treat our hearing loss. The lack of stimulation of our brain, at least theoretically, seems to be capable of altering the rate at which the degeneration will occur and actually whether you get diagnosed with Alzheimer's disease or not, and so, while we may know people who don't want to have their hearing aid in, it's actually very important for people to wear their hearing aid. It alters their Alzheimer's risk, and apparently significantly. It would also add to the list that there's a lot about sleep that is very important in terms of well everything, but certainly Alzheimer's disease risk. It turns out these things that we have in our brain the beta amyloid, the phosphorylated tau protein. We have systems in our brain that clean those up. Right now it's happening in every single one of us every night when we're asleep. We have a machinery that actually has as its job to go clean these things up, but they only do it during certain stages of sleep slow wave sleep or our deep sleep and REM sleep, partially, mostly the slow wave sleep. So sleep is actually extremely important.

Dr. Michael Koren: 26:51

So you see, I wasn't joking when I said we can flush things out, yeah right. So just in terms of obesity, obviously that would be a concern for a lot of people. Is it truly obesity that's the risk factor, or all the things that run with obesity, like cholesterol issues, high blood pressure, et cetera? Has that been teased out or in combination thereof?

Dr. Steven Toenjes: 27:14

And elevated inflammatory just general inflammatory markers and things like that.

Dr. Michael Koren: 27:20

That's been a little it's a lot. There's a lot to be obesity, so unpack that. So when you see these articles, sometimes they don't break down the underlying causes of things, it's just a general association.

Dr. Steven Toenjes: 27:33

So if you don't want to go to the gym and start exercising and one day you're thinking you're going to skip, just remember don't skip. You don't want to, you're trying to hold off Alzheimer's disease.

Dr. Michael Koren: 27:44

Yeah, so we're back to faucet again, and so we now have a basic understanding of what the concerns are. And they ask you are there treatments available? So just run down quickly what some of the treatments are.

Dr. Steven Toenjes: 28:00

So it's useful with therapies to break into general categories Symptomatic relief therapies and disease modifying therapies. Symptomatic relief therapies are something that improve a symptom but don't alter the overall course. The example that I give to people is if I bump my knee real bad and my knee hurts severely, I could take a pain medicine to try to help with my knee pain, but the pain medicine is not going to fix my knee. That would be very different than a medicine that fixed my knee or sped up the rate at which it improved itself. So always keep in mind when we're thinking about medications is this a disease modifying therapy? Is this a symptomatic relief therapy? For decades we have had some symptomatic relief therapies listed up there at the top. Most commonly Donepeiol gets used. But in that class of therapies there are other medications Galantamine and Rivastigmine that can help with some forgetfulness in an Alzheimer's patient. It can help other degenerative conditions as well, but they don't fix anything and they don't alter the course. If they're beneficial and someone's tolerating those types of medications, it is worthwhile using them. They have had demonstrated efficacy in the stages of mild dementia or later. They have never been demonstrated to be of any real benefit while someone is in a mild cognitive impairment state. Let's just differentiate those two names or labels on severity of a cognitive deficit for a second. What does dementia mean? Dementia simply refers to the severity of a cognitive deficit. It means that the cognitive deficit is significant enough that it is influencing, and it's the cognitive limitation that is the reason why a person is failing and having trouble doing their activities of daily living. Activities of daily living are the things we just do in everyday life.

Dr. Michael Koren: 30:14

We go to the store snaking out of drain.

Dr. Steven Toenjes: 30:17

Right. We make a sandwich, we clean up after ourselves, we take our medicines, we drive, and so some of these activities of daily living are harder than others. But if the cognitive deficit is getting in the way of activities of daily living, that is what dementia means. It does not mean you have Alzheimer's disease. If you drink a fifth of vodka every day, you'll eventually have a dementia, and that's not Alzheimer's disease, that's alcohol-related.

Dr. Michael Koren: 30:46

No, it's good vodka.

Dr. Steven Toenjes: 30:47

No no. It's not true. So just to keep that straight, Memantine is a unique substance. It has had some demonstrated efficacy, more once we've gotten to moderate stages of dementia and later. But it's a very well-tolerated and a very safe medicine and so it is often used. There's a low threshold to use the Memantine in the community. Now, down at the bottom, aducanumab, or aduhelm and lecanamab or lekenbi. Those are very different medicines. Those are medicines that have as their goal slowing down the decline of Alzheimer's disease in a human that has the disease. I'm really just going to talk or mention more lecanamab or lekenbi. Adicainamab, you may be aware, had a conditional or emergency use approval. That was a fairly controversial approval within the FDA. Lekenbi is not in that category. Lekenbi is FDA-approved as a disease modifying therapy for mild cognitive impairment due to Alzheimer's disease or mild dementia due to Alzheimer's disease, and in the studies with lekenbi just so you understand kind of the general ballpark figure of its efficacy lekenbi slowed down the cognitive decline by 27%. It's something that has a medication that has risks associated with it and so those benefits are something that certainly come with risk. It's a relatively expensive medication that you've got to go get infused every two weeks. Very expensive Very expensive and we have a lot of monitoring to monitor the risks of. But it's the first clear indication of a true disease modifying therapy for Alzheimer's disease. And so now the entire approach to the disease of Alzheimer's disease has to change. We can't just say OK, it's just blow off. This is normal age-related cognitive change Because, remember, you can have Alzheimer's and have no symptoms and you're going to have Alzheimer's for a long time before you do have symptoms. And once those symptoms start, and once those symptoms begin, they will be progressive. They will start off very, very subtle. It turns out that it's probably the best time to take a medicine like LeCambi up front. It's less risky and appears to be more effective the earlier in the stage of Alzheimer's that we have treated. We've had ongoing trials with the amyloid hypothesis for decades. I remember our residency program being in part with the amyloid Alzheimer's vaccines, which are an approach at amyloid attacking amyloid. Lecambi is an antibody that attaches to and destroys that pathologic beta amyloid that is precipitating in our brain and it clears it out. It uses our immune system to clear it out, but we can get that beta amyloid completely out of someone's brain who has Alzheimer's disease. What has been refined through the years with ongoing research, is how to do that. How do you do that safely, or at least relatively safely and when do you do that? And that's what has taken decades to come to pass. With Lekenbi as the first true traditional FDA-approved disease-modifying therapy for Alzheimer's disease and this is the first of a slew of medications that are going to be coming. I will be surprised if there's not a second one approved this month or next month. It doesn't have a name yet. It's a generic name as donanemab, and there will be more that will follow, and so it's a very exciting time. It's been a very long time coming for us to consistently strike out with disease-modifying therapies, but now we're in a scenario where we do have the option for disease-modifying therapies.

Dr. Michael Koren: 35:26

Yeah, so very, very exciting times. So one of the things that I'll point out you can impress your friends with this knowledge is that the last two things on this slide and with MAB, which stands for monoclonal antibodies, so you can look at your friends' medicines and figure out whether or not they're on a monoclonal antibody or not. And the mechanism of that is monoclonal antibodies are these molecules that are in all of our bodies that have been therapeutically developed to target one protein and to combine with that protein. In many cases so it can't combine with other things. So these drugs can find the protein that forms the amyloid plaque and prevent it from interacting other places. But I think it's also fair to talk about non-pharmacological treatments, so just a quick note on that.

Dr. Steven Toenjes: 36:17

Certainly, you know, historically, before we actually had the option of discussing true disease modifying therapies in the Alzheimer's world, you know we routinely would always point out it's not that there aren't things that don't alter the rate of decline. There have always been things that significantly alter the rate of decline and quite simply those are being active physically and mentally, sleeping, eating healthy, various diets like the Mediterranean diet we like to push, but real, clear data on regular cardiovascular exercise can objectively improve your memory, probably by the way that it changes your sleep. Right, but that's just actually my opinion on how that occurs. The bottom line is that regular cardiovascular exercise does can improve memory and will slow down the decline of even an Alzheimer's disease patient. It's helpful for people to understand what we mean by regular cardiovascular exercise. What would you say? Regular cardiovascular exercise means 30 minutes a day, four days a week. Yeah, so sustained heart rate, 30 minutes. It doesn't mean I go walk the dog because you're not walking the dog. That dog's walking you, right, that dog stops periodically. They're checking their p-mail and that is not exercise. Okay, you got to be walking at a good clip and you got to not stop for a half an hour. That's what regular cardiovascular exercise means and it doesn't just help cognitive decline, it helps our cardiovascular risk for sure being cognitively stimulated, being active, not doing things that are very passive, like watching TV. You can be creative. You can turn passive things into active things. Turn the show off then talk about and discuss what was the topic of the show or something. Being active in volunteer work, doing things that seem to be important to you. The good news is you get to pick. You can pick what you like. You get to listen to whatever music you want to listen to, but actually listen to it, actively listen to it. I like to listen to the bass line because I played the bass in the garage band growing up, so I actively listen to a bass line. That's what I'm listening to often. When I'm listening to music, I'm sure you're listening to the piano.

Dr. Michael Koren: 38:59

Yeah, so I do play keyboards and I would definitely be focused on that. But let me ask you when we were growing up, there was some discussion that hard rock music actually caused brain damage, and now you're telling me that it reverses brain damage. Is that what you're saying? So, if you can comment on it, the different types of music make a difference. Now, if I listen to Led Zeppelin versus Mozart, am I doing something good for myself or bad?

Dr. Steven Toenjes: 39:28

I think that where I think the biggest utility would be. I mean, if you're an individual that Led Zeppelin really relaxes you, then that's going to be the best for you. Most of the time, the hard rock music is not really going to relax somebody in lower stress levels and lower stress hormones and things like that like classical music will generally do that. But there are people that classical music is really going to piss off and it's going to make them angry and that's going to raise their blood pressure and it's going to raise all of their stress. So that's the point about. When we get older. You're at a stage where you get to pick what it is you like. If you like to walk on the beach, well, what do you got to do today? Go to the beach, put your sunscreen on, wear your hat and walk for 30 minutes on the beach and recharge your batteries. That is so good for your brain, it is also good for your heart.

Dr. Michael Koren: 40:22

Absolutely. We strongly advocate that. So there are no randomized clinical trials between Led Zeppelin and Mozart. Sorry, not that I'm aware of, but you are very involved in randomized clinical trials, so let's talk a little bit about that. So you mentioned the aducanumab controversy and, in a nutshell, there was barely any benefit. But the FDA said that there's been so much money that's gone into this research that we have to approve something, and they actually approved it, even though the advisory committee suggested that it probably shouldn't be approved. So is that a fair summary?

Dr. Steven Toenjes: 40:58

That is. I think one of the things that was interesting to see through the COVID pandemic was to see things like FDA advisory panel become something that folks in the general public were aware of existed. The FDA will get together a panel of experts that are identified experts in certain fields and have them come to a resolution on. You look at, you're an expert in this field, you study this, you know everything about the process. Would you recommend that our FDA approve this medication? And one of the big controversies with aducanumab was that the advisory panel not just recommended not approving the drug, they unanimously recommended not approving the drug and most of them quit after they resigned. They said you're not going to listen to this, but the did better. The canumab has clear supporting data.

Dr. Michael Koren: 42:06

And I think this is the supporting information here.

Dr. Steven Toenjes: 42:10

So the big. The main graph on your left is a graph of a CDR clinical dementia ratings. It's just a scale to rate the severity of cognitive deficits, and what you see is the canumab, the yellow line, did not decline as fast as the placebo group did, and so what you're looking at there, at the end of an 18 month trial, is a 27% difference in the rate of decline as measured by this particular disease rating scale. So clearly effective. This is a randomized placebo controlled trial. People did not, and their evaluators do not know what they're on. The patient doesn't know what they're on. Nobody knows what they're on until the the elmelobe's.

Dr. Michael Koren: 43:02

Do we have patients participating in this in Northeast Florida?

Dr. Steven Toenjes: 43:04

We were. I am not aware of the canumab studies being in North Florida, but we've done a lot of this work. We've certainly been a big part of adicanumab trials and then the drug that'll probably be approved next month done adimab. We've got a lot of people in those trials.

Dr. Michael Koren: 43:24

We've been very involved in that research, so the reduction in amyloid burden on pet scanning is quite impressive.

Dr. Steven Toenjes: 43:30

It is, and so I think that that's just helpful to understand that lecanumab does clearly get that beta amyloid out of a human's brain, and that turned out to be beneficial in terms of slowing the decline.

Dr. Michael Koren: 43:44

And this is the other product that you mentioned, lecanumab, which was we've been very involved with in terms of the research for this product. So, again, and if anybody in the audience is part of those studies, but we appreciate if you were.

Dr. Steven Toenjes: 43:56

So just the tidbit down in the green lettering there that I kind of alluded to this earlier. You know the part about additional subpopulations when analyzed, looking at the earliest patients, okay, early cognitive or early mild cognitive impairment, and we can also gauge where someone is. If we can get quantified amyloid PET, okay, which we should be able to start getting in the community. You cannot get that right now outside of a research trial, but we're really trying to get the different health systems. I'm not aware of whether Mayo is capable of doing that, I'm not aware that they can, but other places cannot quantify amyloid burden outside of a research trial, but it's just software from GE that just needs to be loaded into precision and Baptist computers and then we'll be able to measure densities. And what that mentioned was that in the very earliest patients dananumab slowed the cognitive decline by 60%, so that's more than doubling the length of time that someone remains dependent, living on their own, capable of driving, and so it makes it is possible to make a very significant difference.

Dr. Michael Koren: 45:24

And these are pictures of amyloid PETs. You get a sense of it. And these are not quantified at this point. It's more qualitative assessments.

Dr. Steven Toenjes: 45:32

In the research trials, they are, and most research trials they are, and you're really just looking for the presence of the beta amyloid really in our cortex, which is the bottom left picture. There it's showing that that is actually precipitating in the cortex of our brain, not the sub-portal regions, which will have some beta amyloid in it.

Dr. Michael Koren: 45:55

So let's go back to our case study. So they return a few weeks later and you have to break the news. So in this case, you're telling them that in fact, their test results are positive and that there was some cognitive decline and that you have a positive amyloid PET. So what are the next steps for the plumber and his wife?

Dr. Steven Toenjes: 46:19

So remember, pathologically we were looking for beta amyloid, we were looking for tau protein. Historically a strict diagnosis of Alzheimer's is going to include the proving of a degenerative condition, meaning a progressive decline. Clinically that can be deciphered. There are other ways to determine that that there's beta amyloid pathology and that there's tau pathology. Now we don't necessarily need to do that because in this scenario we'll assume that we've gone through cognitive testing with Fawcett and the pattern was actually an amnestic cognitive decline. Meaning the people who do formal and detailed cognitive testing tested faucet and were suspicious that one of the main problems or main deficits in terms of her cognitive function was actually that her memory has a problem and that's a challenge to do. We call that testing, neuropsych testing. Usually there are various ways to do that. But in this scenario if we're worried that we have a mild cognitive impairment state she's got complaints it's primarily a memory problem. We think that this is an amnestic cognitive decline. And now we've proven that there is amyloid pathology in someone's brain. Remember we stated that just because they're amyloid positive doesn't mean with 100% assurance that the person has Alzheimer's disease. But the likelihood that this person in this now example has Alzheimer's disease is very high. It's high enough that in clinical trials we just assume that this is actually Alzheimer's disease and this is all that is necessary to move forward with anti-amyloid treatment for Alzheimer's disease, and so we would talk about the conservative approaches to altering the course. Physical activity, mental activity.

Dr. Michael Koren: 48:26

But there are options now that weren't available three years ago.

Dr. Steven Toenjes: 48:30

We would talk about the possibility of participating in research trials and we would very clearly discuss Lekembi that we have mentioned as an option, one of the most important things for us to make sure that we point out. And when you watch the Lekenbi and then, if donanemabs approve their commercials, it's always interesting to listen to the part of the commercial where the side effects get listed. The side effects are going to include and they do include brain edema, brain hemorrhage, death. Those are three of them. Those are the only three that we really need to talk about.

Dr. Michael Koren: 49:09

Right. So my suggestion is don't read about the side effects.

Dr. Steven Toenjes: 49:13

So death is a possible side effect and that is uncommon. In Lekenbi's trials there were three deaths in their trials with thousands of people in their trials. I'm not so sure really consider one of those actual Lekenbi deaths. How many in the placebo group? I don't think the placebo had any but people in that. It's a year and a half long study and so that's a good point. The brain edema and the brain hemorrhage does happen in the placebo group, but it clearly happens at a higher rate in the treated group and that rate can be between 20 to 40% of patients. Most of the time the edema or the hemorrhages that are forming are completely asymptomatic. The person has absolutely no idea that this is going on in their brain and the only reason that we're aware it's going on in their brain we do repetitive MRIs. When we put someone on Lekenbi, you're going to have several MRIs the first year that you're on that medication because you may not be aware that there are little hemorrhages that are forming and we want to hold the medicine for a while until those things stabilize if those complications are arising. And so it's a laborious thing to consider, but it is clearly an effective therapy and that's why it's approved by the FDA.

Narrator: 50:34

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