Dementia vs. Alzheimer's

TRANSCRIPT:

Michelle
Welcome to MedEvidence Truth Behind the Data. Today we are talking with Dr. Michael Koren and Dr. Steven Toenjes about Alzheimer's disease. Let's first introduce Dr. Koren. Dr. Michael Koren is a practicing cardiologist and CEO and founder of Encore Research Group. He has been principal investigator of multiple trials and has been published in the most prestigious journals. Also joining us today, Dr. Steven Toenjes.

Michelle
He's a board certified neurologist and principal investigator on multiple trials at Encore Research Group. He is a decorated Navy veteran and has been practicing neurology in Jacksonville for over ten years. Gentlemen, welcome today. Thanks for having us. Yeah, I'm excited. This is a good topic, if I remember correctly. I think we have a good topic ahead of.

Dr. Koren
Us, if you remember correctly.

Michelle
Yes, if I remember correctly. All right. So we're going to be talking today about Alzheimer's disease, the breakdown. Dementia versus Alzheimer's. Now, some people think that it's the same thing. What's the difference? Let's go there.

Dr. Koren
Well, we'll let the neurologist jump in. This is definition, and then I'll give you the cardiovascular definition.

Dr.Toenjes
So that and that's a very, very common question. I must hear multiple times a day in the clinic. First, dementia is a term that really refers to the severity of a cognitive deficit. It doesn't really refer to an etiology for that cognitive deficit. So if the cognitive deficit is sufficient enough and in degree that it really starts to impact what we would refer to as activities of daily living.

Dr.Toenjes
Basically, your your ability to care for yourself, essentially that that we would call a dementia. But dementia doesn't really have any reference to the cause. You can have a dementia if you've had Alzheimer's disease for a number of years. If you drink a fifth of vodka every day, eventually you'll you'll have a dementia from that behavior. So the term dementia purely and simply is a reference to the severity of a cognitive deficit.

Dr. Koren
Is there a technical skill that you look at as a neurologist that tells you somebody is either impaired mentally or actually demented?

Dr.Toenjes
There's there's a number of them. But quite frankly, we we really just split up activities of daily living, you know, things like paying bills, driving probably one of your more common technical technically activity of daily living that gets people labeled as having difficulty specifically with activities of daily living is medication administration. If you cognitively can't, you know, manager on medication, that's technically a failure of an activity of daily living.

Dr.Toenjes
So there's not any specific skill, but there are dementia rating skills, there's many mental skills, there's all kinds of skills. And yes, they are basically all have sort of their labels in terms of of of severity, I would say probably most commonly used with the neuropsychologists that do formal cognitive testing would be called the dementia rating scale. And there there are specific numbers that that, you know, get labeled with formal cognitive testing.

Dr.Toenjes
Right.

Dr. Koren
And cardiologists and neurologists work together all the time and kind of bounce things off of each other, because often in the cardiology realm will be dealing with vascular or cardiac reasons for people having strokes in a stroke is usually relatively obvious, although sometimes I'll turn to my colleague and say it's kind of something funny going on here. Can you help me figure out if this is a neurological event or not?

Dr. Koren
And then some more subtle things like people that are just not functioning as well and whether or not there's a connection between what's happening from a cardiovascular standpoint and a brain standpoint. So is agitation just mentioned? Dementia is really, you know, a severe form of brain functioning that's not allowing people to do their basic, basic daily living activities.

Dr. Koren
And one of the first things we do is try to figure out what's causing it. What's a long issue? And from a cardiovascular standpoint, we'll talk a lot about are there blood clots from the heart or from the blood vessels that are going up and causing problems in the brain? And when that happens and we can prove that's the case, we call it vascular dementia, meaning that there's some piece of clot or plaque or cholesterol deposit that's actually causing some mechanical damage to the blood vessels that are affecting the brain.

Dr. Koren
And then there are other categories that don't seem to fall into this vascular dementia category. And that's and that's where we would then would transfer that patient over to the neurologist to look at things a little bit more critically.

Dr.Toenjes
And I think that it would be helpful to consider somewhat the history of the way things get labeled the reason. And you'll still hear patients when I ask, well, what what's been told to you is the cause for the cognitive impairment in your loved one. And the answer is they just have a dementia. Historically, neurologists and physicians in general have not gotten to sophisticated about labeling the etiology.

Dr.Toenjes
And so just a nonspecific dementia is something that has been commonly the diagnosis.

Michelle
Or just kind of like an umbrella, correct?

Dr.Toenjes
Yeah, with no real differentiation between different causes of dementia. And the reason for the majority of that, at least with the most common cause of dementia, which would be Alzheimer's disease, you know, there's largely not been disease modifying therapies. And so what's the need to really differentiate something that historically has been best diagnosed at autopsy? But as as our scientific knowledge in the in our society as a whole, move forward with putative and hopeful disease modifying therapies, it starts to become very important to try to decipher exactly what is the cause of this person's cognitive decline and is it something that we may have some sort of treatment for?

Dr.Toenjes
And so it is important now to not just generally use the term dementia if you're trying to ascribe an etiology and come up with therapeutics, it's starting to become much more important to label the etiology like vascular dementia. The second most common cause of degenerative dementia is Lewy body dementia, and there are obviously other etiologies as well.

Michelle
So back to Lewy Body. What exactly is that? I know my stepdaughter, they said she doesn't have Lewy Body, but because she was fainting and having some like episodes like that, she's in her young twenties, but they already said she doesn't have this. How how do you get to that point?

Dr.Toenjes
So Lewy body dementia is is a at least pathologically a very different dementia from Alzheimer's disease. It's in the class of disorders. We call this synuclein apathy. A lot of the pathologies and explanations for the different degenerative dementias and involve precipitation of certain abnormal proteins or substances within neurons or around neurons of our brain. In quite simply, the way they've been described through the years is how the pathologists see them.

Dr.Toenjes
And when you see Lewy bodies, which are pathological entity that you see on a microscope, which is contained of alpha synuclein in just the right areas of our brain, that is the pathological entity of Lewy body dementia. The clinical presentation or or disorder of of Lewy body dementia has some unique hallmarks that do very much differentiate it from Alzheimer's disease.

Dr.Toenjes
Typically, there will be very prominent and early visual hallucinations. The type of cognitive decline. It's a little bit different than an Alzheimer's disease patient in a Lewy body. Dementia patient will have very commonly associated other disorders like a REM sleep behavior disorder, potentially even many, many years before the onset of the cognitive decline. So it's distinct clinically.

Dr. Koren 
So much of what we do in diagnostics nowadays is is based on imaging, are able to just distinguish these different types of dementia, dementia based on imaging at all.

Dr.Toenjes
So imaging is going to appropriately be split up between anatomical imaging like C.T. And MRI based imaging where you see literally just the structure of of of brain tissue. And then there are additional modalities such as pet imaging, where we're looking at the amount of glucose metabolism per volume, brain tissue. And then there are specific ways to radio labeled pathological entities such as beta amyloid, which precipitates in a number of disorders and phosphorylated tau, which both of those actually have FDA approved SPECT ligands.

Dr.Toenjes
You can use.

Dr. Koren
That clinically.

Dr.Toenjes
Not so much in in while it's available and you could you could obtain that someone would be paying out of pocket for it. It's quite expensive. So it's still in in reality and in use as basically limited to research studies. But you can actually you can also do dopamine transporter imaging that's aspect imaging that we do actually use sometimes and that can help tease out Parkinson isms and Lewy body dementia.

Dr.Toenjes
Being at one of the Parkinson isms could theoretically be helpful in certain situations, but usually that's that's not necessary.

Dr. Koren
You start to do a biopsy and make a definitive diagnosis.

Dr.Toenjes
You wouldn't you wouldn't, you would if that were going to change your management. But it's the presence of it's really not going to change the management. And so no, not at not at this time. We don't get too sophisticated. We stick with clinical criteria to diagnose something like a Lewy body.

Michelle
Is is there treatment for dementia that can reverse it or is treatment just to kind of maintain it?

Dr.Toenjes
So in terms of treatments, it I think is very helpful to split up treatment into different general categories. The first category would be symptomatic relief, and the second category would be disease modifying, meaning changing the course of the illness. In historically, we have had basically symptomatic relief therapies and we're we believe in the research world that we're on the brink of disease, modifying therapeutics, which.

Dr. Koren
Is really exciting.

Dr.Toenjes
And so you have some of some of the therapies for the various dementias will will be thought of as symptomatic relief. And there are many patients that do achieve benefit from the medications that are available. I would point out that I say repeatedly in the clinic that that while there are some controversies and and and we're on the brink of hope for, you know, disease modifying therapeutics, there are disease modifying approaches and there are a number of things that significantly influence the rate of decline for various dementias, specifically Alzheimer's, for sure.

Dr.Toenjes
And those things are are the things that your your doctors are always telling you to do, basically live live a healthy lifestyle, control your blood pressure, remain physically and mentally active, sleep appropriately. Right. Sleep apnea, treat it, things like that.

Michelle
Right. And with over XYZ and with over 6 million Americans believed to have Alzheimer's disease and it's the sixth leading cause of death in the United States. Those are some some big factors to consider. You know, and any doctor you talk to is going to say sleep, eat well and move.

Dr. Koren
And that leads me to my session ending QUESTION. All right. I get that honor this time.

Michelle
Okay? Yeah. Yeah. How about you, Dr. Warren?

Dr. Koren
So is is dementia inevitable? Is everybody going to get something of some cognitive impairment as they get older and it's something that we inevitably deal with? Or are there people who have absolute no signs of it at advanced ages?

Dr.Toenjes 
That's that's an interesting thing to be worried about.

Michelle
Yeah, right, Right. And we are going to do that.

Dr.Toenjes
And lean.

Michelle
Back in the next segment.

Dr.Toenjes
This guy maybe. But there are there definitely have been folks in the medical literature and and intelligent people that who have had the thoughts that you know, a pathology or a process, something like an Alzheimer's is not necessarily a pathology, but a component of aging. And and, you know, in that respect, you you would you would conclude that potentially you're destined to get that particular disorder if you live long enough.

Dr.Toenjes
Now, that may be 110. When you start to develop Alzheimer's, that might be 47. And so anywhere in that frame, you know, that sort of pathology and then the sequelae of the pathology may unfold. But there are there really are people who are at advanced ages and they have a a remarkable absence of of the types of pathology seen in Alzheimer's and for some reason, they also do not have vascular changes at those ages.

Dr.Toenjes
And it's interesting to note that those patients memories will be just as good at 100 as it was.

Dr. Koren
Sign me up for those genes.

TRANSCRIPT:

Michelle:
Welcome to MedEvidence Truth Behind the data. Today we are talking about Alzheimer's disease and I have Dr. Michael Koren and Dr. Steven Toenjes with me. I am Michele McCormick. Dr. Michael Koren is a practicing cardiologist and CEO and founder of ENCORE Research Group. He has been principal investigator of multiple trials and has been published in the most prestigious journals.

Dr. Koren:
Also joining us are some bad ones. Let's.

Michelle:
Dr. Currin. Dr. Steven Toenjes is a board certified neurologist and principal investigator on multiple trials at ECNORE Research Group. He is a decorated Navy veteran which brought him to the Jacksonville area. And he has been practicing neurology in the area for over ten years. Gentlemen, welcome back. We are talking about dementia, Alzheimer's and but what about if it's just something else like we mentioned briefly, maybe old age?

Michelle:
Okay. My kids are convinced that as I age, my memory is gone away. Like Mom, I told you that. Mom. I told you that. How do you not remember every single word I say? And I always say, Well, I have a lot of information coming into my head all the time, but I play a lot of puzzles, and I'm hoping that that really keeps my brain healthy.

Michelle:
But I do forget where I put the keys at times. And I do walk around in circles saying, Didn't I? What did I come in this room for? Dr. Toenjes Let's talk a little bit about that. And Dr. Koren, when do you know when something's really wrong?

Dr. Toenjes:
So that's those are the the general types of complaints that come into the clinic on almost every day. And it's important to understand that there are normal changes that are associated with aging. But we do not lose our memory as we age. If there's memory loss, there is something wrong. There is damage. The difficulty is trying to decipher what someone's experiencing.

Dr. Toenjes:
And is that memory related? There's multiple cognitive domains that we have and they depend upon each other. Memory is something that very heavily depends. For example, on attention. You have to attend to a task to to formulate a memory and retrieve it. You know, one that we hear all the time or people get concerned about or will literally be a reason for a phone call.

Dr. Toenjes:
Some somebody put the milk in the cabinet and, you know, and using that as an example, I just ask where where does the milk go? And the patient will say in the refrigerator. And so that just illustrates that point, that the person knows that the milk goes in the refrigerator. They didn't forget that it goes in the refrigerator.

Michelle:
They just miss not placed it.

Dr. Toenjes:
To what they're doing. And so executive functions are complex, focusing and shifting and focusing attention that so-called processing speed does slow down as we age. And that's normal. That's normal. There's nothing you can do about that.

Michelle:
Good. I'm going to tell my kids that I'm like, this is.

Dr. Koren:
What else to tell them? That you have many more years of memories than they do.

Michelle:
Exactly. Exactly.

Dr. Koren:
So there's more processing time.

Michelle:
Yeah, well, I always heard that if. If I forget something, but it comes back to me, then I'm okay. Like, if. If if I forgot where I put the keys that morning, or if I was going to tell you something and I forgot what it was. But later on that day, I was like, Oh, that's what it is.

Dr. Toenjes:
And so that's those are the sorts of things that we precisely try to decipher with testing like formal cognitive testing or neuroscience testing to try to tease out is are we capable of defining or deciphering a memory problem? Because all of these other issues, like attention issues, are going to look like short term memory problems, but they are not.

Dr. Toenjes:
But when we do find a memory problem, we do start to be and it's purely memory related. You start to be become concerned that someone may actually be in the early stages of a pathology like Alzheimer's disease. And now that we are come into the age of where we're starting to flirt with potential or putative disease modifying therapies for that specific situation.

Dr. Toenjes:
By the way, the most common cause of of dementia as we age, that's that's that's why we're here. And we're talking about these things, such as the kinds of research that's being done and the interesting basic science that that is unfolding with the amyloid hypothesis of Alzheimer's disease.

Dr. Koren:
Amyloid hypothesis. I love.

Michelle:
That.

Dr. Koren:
So, yeah, amyloid is a key word that is critical to a lot of discussions about how we're approaching treating Alzheimer's disease, preventing Alzheimer's disease and treating other medical conditions. So I think it's probably worthwhile to spend a few minutes just explaining to people that amyloid is so amyloid is basically an abnormal protein very, very simply. But how does that become an abnormal protein?

Dr. Koren:
And what we've learned and this gets back to some things we talked about in previous sessions, which is that we now understand that that we have DNA. DNA sends a message to our cells through RNA to make proteins that are made in the ribosomes, and then the proteins are made in the ribosomes, and that reflects the genetics of each individual.

Dr. Koren:
But once the proteins are made, other magic happens. And part of that magic is the way these proteins fold so that they can provide functions and supports the body in different ways, either structural functions or or chemical changes, etc., depending on if they're enzymes or structural proteins or other things. And if they don't fold correctly, even though they're the right material, they're not useful.

00:05:58:06 - 00:06:24:00
Dr. Koren:
So maybe a simple way to think about that. And this goes back to what my mom told me when I was a kid is, you know, if you fold your clothes and you put them in your drawer, you'll be able to find them again. Your drawer won't get all messed up in terms of be able to open it again because all the crumpled clothes that expand if you put them in and then you can open your drawer anymore and you're less likely to find an old grilled cheese sandwich and folded clothes than you would in a closet because you.

Michelle:
Forgot it was there. Right.

Dr. Koren:
Right. So and it's funny, it may sound crazy, but there is actually a decent analogy to what happens with proteins. So I'm speaking a little bit from a cardiovascular perspective now, but amyloid, which is believed to be a critical component of Alzheimer's disease, is also part of other disease processes. In particularly there's amyloidosis of the heart and there's actually an FDA approved treatment for that based on a problem with a protein called Transthyretin.

Dr. Koren:
So something now called transthyretin cardiomyopathy that we just called amyloid. And basically that's a protein that's actually responsible for transmitting thyroid hormone that stops folding correctly. And when it stops folding correctly, it accumulates in the heart. And when accumulates in the heart, you're prone to having arrhythmias and poor heart function and heart failure and can die of sudden cardiac death.

Dr. Koren:
 And now we actually know what enzymes are responsible for that folding process. And there can be treatments now, FDA approved treatments that help the proteins fold correctly.

Michelle:
That's fascinating. Yeah, actually, it's. And that's unbelievable. I picture that DNA structure that you always see the drawing of in half and then kind of unfolding. That's how I picture it in my non-medical brain. Right.

Dr. Koren:
And again, just to make sure everybody's clear on it, the DNA is the blueprint. And the blueprint is turned into a protein through RNA and through ribosomes. And then there are other things that happen to these proteins even after they get outside of the cells. But we're just learning all this stuff and we're starting now to understand that certain people have a genetic reason why these proteins don't fold appropriately.

Dr. Koren:
So, Steve, maybe you can mention what we know about amyloid in the brain and this hypothesis of folding appropriately or not.

Dr. Toenjes:
Well, the reason it's sort of been the amyloid hypothesis of Alzheimer's disease is is pathologically it seems to be one of the first steps that occurs in the process of what becomes an Alzheimer's brain. This abnormally folded beta amyloid protein is precipitating. And that actually is a process that winds up starting decades before a patient with Alzheimer's ever has their very first symptom.

Dr. Toenjes:
And so the area of abnormally folded and precipitating beta amyloid proteins starts building that progresses and is thought to kick off a process that ends in the abnormal folding and then precipitation of another, a different protein called tau protein or hyper phosphorylated tau protein. And as tau protein then starts to precipitate within the actual neurons, that causes them to enter into a process of death and degeneration.

Dr. Toenjes:
But the thought has always been that, however, this occurs, it is the initial step of abnormal protein beta amyloid that kicks off the whole process. Now there's a whole there's a whole basic science world that surrounds this process, and it involves different inflammatory influences on this process. There are there are thought to be things that influence the metabolism within neurons, like glucose metabolism within neurons.

Dr. Toenjes:
And and and the basic science understanding of this hypothesis is where therapeutics have started to then.

Dr. Koren:
Yeah. And this gets into some of the interesting research elements. So because of the hypothesis about amyloid, we're doing more and more studies, looking, using imaging to look at the degree of amyloid deposits.

Michelle:
And that was exactly what I was going to.

Dr. Koren:
Ask the different organs and of course, including the brain. Yeah. And so maybe come in a little bit about that in terms of is this imaging research makes sense? What are your thoughts about it? What's the relevance for the average patient that may be listening to this program?

Dr. Toenjes:
Sure. You know, I am vid pet or really aspect imaging study radio labeling beat amyloid within brain tissue is FDA approved. It is an imaging modality that that can be obtained. It's very almost impossible to get insurance coverage for that but I you know is a pretty strong test. It's really very useful and most useful in being pretty clear that a person does not have Alzheimer's disease if their amyloid imaging is completely normal.

Dr. Toenjes:
The specificity of of embodied pet, you know, is not perfect. There are other things that can they can produce.

Dr. Koren:
Is a good research tool. Do you think.

Dr. Toenjes:
It's a very good research tool? The difficulty, the one of the difficulties through the history of clinical trials, specifically with Alzheimer's disease and and a number of of of just strikeouts, just you know, we've thought something might be useful and then we struck out demonstrating benefit. It turns out when you look back at patients that have historically been in Alzheimer's, Alzheimer's research trials, a lot of them didn't have Alzheimer's disease.

Dr. Toenjes:
And so the research world in many studies and some of the studies that we're actively doing now, you know, include things like amyloid, SPECT, imaging, Talbot, SPECT imaging and of course, MRI based imaging do leave no question whatsoever that the person in the trial has Alzheimer's disease. And so the research world has really jumped far ahead of what's what's clinically and regular use.

Dr. Toenjes:
But all of those are those all of those more sophisticated imaging modalities stand at the ready. They are FDA approved and they are they can be used. You just can't.

Michelle:
Right.

Dr. Koren:
And and Dr. Tim just made a very important point that I'd like to emphasize, which is we're getting into this realm of a patient specific medicine where we understand the individual genetics of a patient and then can apply therapies that are relevant to that particular patient. In previous studies, probably because we didn't have the specificity of diagnosis, we were treating a bunch of people that had the general problem that we thought they could be treated for.

Dr. Koren:
But we're using a therapy that would only possibly have a benefit in a small fragment of that population. So a lot of research studies may be, quote, falsely negative because we're missing the small picture. Because the big picture, Yeah.

Michelle:
So has the Alzheimer's diagnosis gone up or has it gone down for the number of people being diagnosed now with this improved technology?

Dr. Toenjes:
The technology is not necessarily responsible for what's observed and unfortunately, dramatically expanding. I actually recommend people not look into the epidemiology of of Alzheimer's disease, because if you do, you'll start to get very, very frightened.

Michelle:
It sounds frightening. Sure.

Dr. Koren:
Yeah. Well, and also, as we treat other problems successfully, more people will have problems of older age and Alzheimer's would be one of those problems.

Dr. Toenjes:
Correct. If you look at rates of mortality, for example, you know, huge advances with statins and cardiovascular risk reduction in reducing cardiovascular death rate and stroke, death rate and disability. But Alzheimer's has really lagged behind. And so it really is jumping up in terms of, you know, etiologies for disability and death.

Dr. Koren:
So basically when the cardiologist fixed them, then we sent in neurologist and let them become demented with you guys. All right.

Dr. Toenjes:
Thank you.

TRANSCRIPT:

Michelle
Welcome to MedEvidence Truth Behind the Data. I'm Michelle McCormick. Today we're with Michael Koren, Dr. Michael Koren and Dr. Steven Toenjes. Just we are talking about Alzheimer's disease and now the Hubble values of Aduhelm. But first, Dr. Michael Koren is a practicing cardiologist and CEO and founder of ENCORE Research Group. He has been principal investigator of multiple trials and has been published in the most prestigious journals.

Michelle
Dr. Stephen Toenjes is a board certified neurologist and principal investigator on multiple trials at ENCORE Research Group. He is a decorated Navy veteran and has been practicing neurology in Jacksonville for over ten years. Gentlemen, quite great conversation we've been having today. If I remember correctly. I think we've really talked a lot about.

Dr. Koren
The conversation today.

Michelle
We've had a good conversation today about that. But now treatments or research trials. Dr. Koren, take us tell us a little bit about Aduhelm.

Dr. Koren
Sure. Well, I'll just start by mentioning the fact that both Dr. Toenjes and I work at Jacksonville Center Clinical Research. This is a group of physicians. It's a physician based group that runs clinical trials outside of our practices. And we have about 100 doctors in the area that participate. And we are doing studies in many different areas. My concentration would be cardiovascular.

Dr. Koren
I got very involved, of course, in the COVID 19 vaccine studies because of my expertise in running clinical trials. But Dr. Toenjes has been instrumental and has done great work for us in Alzheimer's, in migraine headache and some other areas, but about to get some Parkinson's stuff up and going so excited about that. So we've been fortunate. This physician group has developed a reputation internationally, now is doing some really good work in testing all these things, as both Dr. Toenjes and I will attest to.

Dr. Koren
It's great to talk about the theoretical elements of what should and should not work, but at the end of the day, what happens in clinical trials tells us what in fact does work, and we're never as smart as we think we are. So we have to run the clinical trials to really see whether or not our are brilliant hypotheses turn out to be actually true.

Dr. Koren
And so that's a neat thing that we do every day. And patients, you know, typically really enjoy the process and learn from the process and get very tangible benefits from the process in many cases.

Michelle
And they get to be a part of it too. So they feel like they're giving back and doing something to move medicine forward.

Dr. Koren
Yeah. And so in medicine, there are areas that make great progress fairly quickly. So Dr. Toenjes mentioned statins and we've had discussions on on this program about some of the amazing breakthroughs in lipid treatment. And they've made a huge difference. And just remind everybody. Cardiovascular death rates dropped in the U.S. by 60% between 1980 and 2010.

Michelle
That's huge.

Dr. Koren
And that was due to the fact that we we had this great research and largely due to preventative cardiovascular therapies that became prevalent.

Dr. Koren
Dr. Changes has been part of migraine studies, and we're doing a great job in migraine compared to some other areas. But Alzheimer's has been a toughie. It's been a tough area and a lot of companies have spent a lot a lot of money doing research in this area with a lot a lot of not great results. And recently it was a company called Biogen that developed a monoclonal antibody to try to prevent the development of amyloid plaques.

Dr. Koren
That had pretty mixed results. And there was a bit of a controversy about FDA approval of it. And I'll hand it off to Dr. Toenjes to give us a little bit more insight into this this particular product and the current controversy.

Dr. Toenjes
Sure. Thank you. So Aducanumab or Adam, is an FDA approved therapy putatively a disease modifying therapy for Alzheimer's disease. It's the first Alzheimer's disease drug to gain any type of FDA approval for a long time, I think since 2003. There are some controversies that surround it. What Aduhelm is, is an antibody that very specifically identifies pathological beta amyloid.

Dr. Toenjes
And through the years of study with the drug, clearly does remove beta amyloid from brain tissue. I think that that's something that can clearly be concluded from the available evidence. The controversy comes in when we tried to determine is there clear and convincing clinical evidence, Do we actually see the outcomes that we want to see? And there were a couple of large studies that were done and historically, we won a couple, at least a couple of separate, well done randomized placebo controlled trials with corroborating results and one of biogen's trials, there did appear to be some meaningful, potentially meaningful clinical efficacy.

Dr. Toenjes
And in the other trial, there was not. And therein lies the the controversy. Now, when we dive into controversy, everyone starts to express their opinions. And in the bottom line is, is that you just have to look at the data and the science isn't controversial. The interpretation of it is what's controversial.

Michelle
How long are the trials?

Dr. Toenjes
They are generally trials that are going to go on for a year.

Dr. Koren
Okay. So I'll give you just a little research insight, a little tidbit, how you know that this is a monoclonal antibody. When you see Aducanumab, it ends with the letters MAB, which is my monoclonal antibody. So for if you want to impress your friends and look at the generic name of a drug and determine if it's an antibody or not, just look to see if ends with MAB.

Dr. Koren
And then for the advanced class, if it ends with you, maybe it's a human monoclonal antibody. So. All right, You want to impress your friends? Say, not only is it a monoclonal antibody, but it's a human monoclonal.

Michelle
Well, I think the word monoclonal antibody was kind of like a buzzword that we've had with COVID as a treatment. And that's the first time I really ever heard of that term. So I appreciate the explanation. Shannon, When something ends it, it may be totally make sense to me, but but it makes sense that you're this is what you're using for your trials, right?

Dr. Koren
And the beauty of a monoclonal antibodies is they can be developed to specifically target a protein. So they're not going to hit random things. They're going to just hit one thing. And so when we use small molecules like pills, they can have what we call off target effects. They can go into different tissues, they can do different things that may not be what's intended.

Dr. Koren
But for monoclonal antibody, they're designed just to hit one thing.

Michelle
So they will go through the system and just attack that one thing. It's like like it has like a laser focus on on where it's going.

Dr. Koren
One thing that's going to fit into the monoclonal antibody. Okay. So it's kind of like a very, very specific key.

Dr. Toenjes
And and that's exactly what advocate of MAB is. And there are other antibodies  in clinical trials in in large phase three stages for other amyloid based antibodies. And I think that it's helpful for people who are either have loved ones or are themselves living with a disease of Alzheimer's. This is a you know, this this the controversies here really hit home.

Dr. Toenjes
And it's it's not a question of whether we can remove beta amyloid out of the brains of humans with with Alzheimer's. We can do that. A number of the antibodies have been demonstrated to clearly do that. The question is, is how exactly do we do that? At what stage of the disease should we be doing that? How safe is doing that?

Dr. Toenjes
And does that translate into actually slowing down the course of disease? There are there are major controversies about whether what was seen, particularly in in Biogen's studies, were those clinically relevant. The whole the whole science of trying to evaluate someone's cognition and then evaluate how it changes is in itself difficult and and I would say controversial. When we do, I trial, there is going to be an identified primary endpoint.

Dr. Toenjes
You're going to predefined this is what we're trying to define were an effect on. And in their trials it was something called the AIDS cog some of boxes. We don't need to talk about exactly what that means, but it's just a way to assess cognition and function and the AIDS cog. Some of boxes in and of itself has some subjective interpretation to it, and therein lies some potential controversy.

Dr. Toenjes
The the reviewers in the medical literature that you'll read, I'd describe the the the Aducanumab studies. Even if you assume that the level of effect on AIDS ecog sum of boxes was actually there, that's not really what we deem a clinically relevant outcome any way. That in itself is also a controversial opinion. That would be an opinion. Who would be arguing against the approval for aducanumab for the general public?

Dr. Koren
Yeah. I'm sorry, just to jump in. Also is the other part of the controversy is really the role of the FDA.

Dr. Toenjes
Correct. That's what I yeah, I was going to go back in because you mentioned the FDA and COVID and it has been very interesting to see how COVID has influenced the general public's understanding of what happens at the FDA. They understand phase three trials. They understand safety and efficacy as main focuses in. And so I, I that is a real plus of something like our learning experience through COVID.

Dr. Toenjes
Unfortunately, when things are within the governmental realm, they are also potentially influenced by controversial behaviors. And so that that is the unfortunate part of of some of the controversy with that of cane of MAB, because patients that I see in their loved ones that I see in clinic, when you start talking about the potential risks of a medication like Aducanumab, which are very real, if there is some uncertainty with regard to our society's watchdog, which is the FDA, that really pulls the the rug out from underneath your ability to to treat patients.

Dr. Toenjes
So the controversy is is unfortunate, but we were just going to have to deal with it and move forward.

Dr. Koren
Yeah. So some people think that the FDA role should be to make sure that stuff is basically safe and the FDA shouldn't get that much involved in terms of determining how good the drug is.  And so in this particular case, this drug, everybody agrees, is, you know, it's okay. There's some potential benefits. If you look at it the right way, you get the right light at the right angle and the data look.

Dr. Koren
Okay. So it's not something that blows your mind in terms of how efficacious it is, like the COVID 19 vaccines, which was clear cut. On the other hand, the FDA determined that this basic safety was good. There's potential side effects, but typically the basic safety of monoclonal antibodies is good because they're very, very specific to the target and they don't do a whole lot outside of hitting the target.

Dr. Koren
So that that was the FDA opinion. And in this particular case, the FDA went out of their way to say that Alzheimer's research has been so difficult, that part of the reason we're approving this is so that the manufacturer can get some money to do further research, because if you keep on trying to do research and you never get a drug on the on the market, you'll never have a return on the investment and they'll never be a reason to do more studies.

Dr. Koren
And I think that was a big part of the controversy. They say that's not the FDA's role to try to support the drug companies. The FDA should be just giving us the facts and they can even decide to approve something. But just say, well, it's not that great, but it doesn't kill you, you know, that sort of thing.

Dr. Koren
And in this case, they went out of their way to say that they they were approving it because they wanted to encourage further drug development in this area and they wanted to be an income source. And then this falls on the payers and the parents of to say, okay, well, they said that the FDA is saying, no, this isn't a great drug, but they still want us to pay these outrageous sums.

Dr. Koren
How much is this drug?

Dr. Toenjes
Well, when it initially was approved, the price tag was 56,000. And then for that's the that's the administration of the drug. There are other costs. Yeah.

Michelle
But is that covered by Medicare?

Dr. Toenjes
When we talk about that, if it's not 56,000, Biogen did some recalculate the case and they lowered the price, I think, to 5550.

Michelle
Okay.

Dr. Toenjes
So they know they passed.

Michelle
All right.

Dr. Toenjes
There are sophisticated means by which we do calculations on how much a drug is worth. And those estimates were more around three or 4000 per person. And after the backlash and and publications like what I just alluded to by Biogen did lower the price of the drug. And they they chopped it in half and half. And so it is approved.

Dr. Toenjes
It is the initial statements from Centers for Medicare or Medicaid Services is that the drug will be covered with a big caveat. Patients have to be in a qualifying study. While many people would still consider the therapeutic, quote unquote experimental, it will be covered if a person's in a qualifying study.

Michelle
Yeah, I was going to say you probably had to check a lot of boxes.

Dr. Toenjes
And we have to understand it's FDA approved to reduce the load of beta amyloid in the brain of a patient with Alzheimer's. It's not FDA approved to alter the clinical course of Alzheimer's. And so you have to look at the fine print of exactly what the FDA said. What does this do? And it does do what the FDA said it does.

Dr. Koren
So the take home message for the audience is that if you forget your keys, you better save your money. 
 

TRANSCRIPT:

Michelle:
Welcome to MedEvidence Truth Behind the Data. I'm Michelle McCormick. Today, we're talking with Dr. Michael Koren and Dr. Steven Toenjes as we are discussing Alzheimer's disease. And what does your gut have to do with it? Very interesting. First of all, let me introduce Dr. Michael Koren. He is a principal investigator and cardiologist. He's a CEO and founder of Encore Research Group.

Michelle:
He has been with them for as many years. How many years, Dr. Koren?

Dr. Koren:
We started the company in 1997.

Michelle:
There you go. All right. And you've been published in some of the most prestigious journals. Our other guest today is Dr. Steven Toenjes. He's a board certified neurologist and principal investigator on multiple trials at ENCORE Research Group. He is a decorated Navy veteran and has been practicing neurology in Jacksonville for over ten years. Well, gentlemen, great discussions today about this deadly disease that 6 million Americans face and one of the top causes of death in the United States.

Dr. Koren:
This time, our second just talking about how devastating can be to some families and how it stresses people and the resources involved in treating these folks and keep them out of trouble.

Michelle:
Frustrating for loved ones, too.

Dr. Koren:
It's definitely an issue that has a lot of families very, very concerned.

Michelle:
And if there's any hope in trials and drugs, you know, we we had a very good conversation about that as well.

Dr. Koren:
Yeah. You know, we talked about at a Aducanumab, a monoclonal antibody for a human monoclonal antibody that is directed to toward clearing these amyloid plaques in the brain. And we were starting to talk about other new research and some of the lessons learned from this particular study. We mentioned the fact that there is some controversy about this particular product because it may not have great efficacy, but was still approved by the FDA.

Dr. Koren:
True.

Dr. Toenjes:
And, you know, remember where there are other antibodies in. So exactly how to how to administer these therapies and when to do it is something that's been going through the refinement process for 20 years. And so hopefully we're about to see some of the fruits of all of that labor. But there are other other studies where we have, you know, other active Alzheimer's trials that are ongoing.

Dr. Toenjes:
One particular interesting one has a little bit of the flavor of this buzz that we say the gut brain axis. There is a therapy that's currently approved by the FDA in China or their equivalent of the FDA for Alzheimer's disease. And it's really in oligosaccharides. That's an extract from brown algae, actually, that is designed to alter essentially our GI flora, the gut flora, and manipulate it in a way that influences how inflammation occurs at a distant site.

Dr. Toenjes:
And that being our brain. And as it turns out, there are a number of areas of research that are that are investigated, how we can influence a very important flora of bacteria in our gut and influence other parts of our body, such as deleterious, inflammatory responses and Alzheimer's.

Dr. Koren:
Curious about the Chinese approval, was that based on good clinical trial data or less good in your opinion?

Dr. Toenjes:
I political statements about. I think you're right. I think I think that it's comforting to know. I think for our general public, I'll say it this way that if you want to have a therapeutic FDA approved by the FDA in the United States, you have to do this study under the watchful eye of the FDA and they reserve the right to audit you at any point in time that they want.

Dr. Toenjes:
And you better have your ducks in a row. And so, you know, just quite frankly, I know nothing about Chinese equivalent of the FDA and and the general public here in the United States would would I think it would be safe to say, not have a whole lot of confidence. Processes. Yeah. Those are studies that need to be replicated.

Michelle:
It sounds like a very intense probiotic.

Dr. Toenjes:
It's so with a quote unquote, probiotics. There's there's a couple of general ways you can approach that. You know, this is an oligosaccharides. It's not actually bacteria. There are some therapeutics that are actually bacteria that are swallowing a capsule of different types of bacteria to try to have them influence the population in your gut. But this specific study is in oligosaccharides.

Dr. Toenjes:
That's an extract from brown algae. It's not an actual bacteria.

Dr. Koren:
Okay. So I guess replace should define the microbiome for folks in understand that. Let me get a little jargony here.

Dr. Toenjes:
So the what our intestines are are loaded with bacteria, and those bacteria are very important to our own function and they can go awry and make you quite miserable. And most people have probably had the experience of altering their gut flora with antibiotics and have torn their GI tract up or gotten other complications and allowed deleterious organisms to take hold and start to grow.

Dr. Toenjes:
Most people have heard of of C. diff as a complication of antibiotics. That's just tipping the balance in the wrong way for a particular bacterium that can kill you. It can be so severe and so, you know, learning a lot about the way that we can control or influence one of the most important parts of physiology within our body.

Dr. Toenjes:
That actually has to do with other organisms that live within our body.

Dr. Koren:
So just a little bit of an aside, but it's interesting in terms of how science evolves and how thinking evolves is something that I share with some of the staff earlier in the week, which is when I was in high school, I used to play Trivial Pursuit. And one of the questions was what's the largest organ in the body?

Dr. Koren:
And the answer was the liver. And there was a solid organ that was considered the largest organ in the body. Then I went to medical school and they asked the question. I raised my hand, Oh, it's the liver. They said, no, it's the skin to skin. Even though you don't think of it as a solid organ is everywhere and it has a lot of biological functions.

Dr. Koren:
And that's actually the largest organ in the body. And so that's cool. So I got into cardiology, I was in my cardiology fellowship and they said, What's the largest organ? The body? And I raised my hand and I said, The skin. So it's the endothelium, which is what lines all the blood vessels everywhere in the body. So if you add up all the cells, in the end, the thallium, it's equal to or greater in volume than the skin.

Dr. Koren:
And recently I was at a conference and they said, what's the largest organ in the body? And I said, The endothelium. They said, No, it's the microbiome.

Michelle:
Oh, killing it way down here. Right.

Dr. Koren:
And so the actual ways of all these bacteria is could be five or ten lbs worth of weight in a body that's responsible for these very, very interesting functions. Obviously, that the way our GI tract works is is importantly regulated by the microbiome. But it turns out there may be a lot of other things, including the inflammatory states of our body and the ability to affect certain proteins, including some of these unfolding concepts that we talked about earlier.


Dr. Toenjes:
I like that story. The and I, I would have I would follow that up with with a reference to a joke. Okay. Every different specialty in medicine, we have jokes about the specialty. And the jokes are a little bit true. And within the.

Michelle:
Business, jokes can be.

Dr. Toenjes:
A little.

Michelle:
Bit funny.

Dr. Toenjes:
Right? And within the neurology world, I think that our our historical joke is a historical joke. That's not really true so much anymore. But this is the joke. So I ask you, do you know how many neurologists it takes to change a light bulb?

Michelle:
I would say none. Give it to the other guy in the room to do.

Dr. Toenjes:
The answer is we can't change a light. And that's the silliness of it.

Michelle:
Right. Right.

Dr. Toenjes:
Realistically, with the explosion of therapeutics and all of these things that we're talking about with research, that's not that's becoming a not so accurate joke anymore with the explosion of therapeutics, particularly in the neuroscience world. And, you know, that's why we're so hopeful with with the things that we've been discussing here, particularly therapeutics as it pertain to Alzheimer's and the research which is ongoing.

Michelle:
So, All right, back to the original question then. What does our gut have to do with it?

Dr. Koren:
So we're running clinical trials as we speak to determine whether or not changes in the microbiome will help memory. And somebody can call us, and if they're interested, we can get them involved in the program as we speak. And it's one of many approaches that are being looked at in terms of understanding this phenomenon of of how different parts of our body interact with each other and affecting one can have positive influences in other parts of our body.

Dr. Koren:
And, you know, there are many lessons in medicine that have have taught us that, in fact, these things could can have a huge impact. So you just and this is a little bit off subject, but is somewhat relevant is in congestive heart failure, which is an area that I've worked in for 30 years. We've gone from talking about using devices to using pills to back to using devices as the best way of treating it.

Dr. Koren:
And it has to do with increasing understanding. And sometimes I hear patients say, well, you guys keep on changing your mind about what's best. Well, when I change your mind, we're just getting better and better data and responding to the better and better data. So, you know, for example, one of the huge issues in clinical medicine right now is how to keep people out of the hospital that have congestive heart failure.

Dr. Koren:
And we we've known that if you're really, really compulsive with all the treatments, then you tend to stay at the hospital. But that's hard for a lot of people. So one of the interesting things that that again, connects different parts of the body and that's why I'm bringing this up, is we're working now on an app that a person can speak to to determine if they're having a congestive heart failure or failure exacerbation is their CHF getting worse?

Dr. Koren:
They said, well, what is their voice have to do with anything? Well, think about it. If there is swelling or edema in your voice, the tone may change. That would be hard for the average person to pick up at a computer may pick it up. A computer could also pick up how many words are in a sentence between voice, between breaths.

Michelle:
And if breaths can be labored? Yeah.

Dr. Koren:
Yeah. But just counting the number of words that you speak between breaths is something a computer can do relatively easily. And that changes in congestive heart failure. So again, there are things you would never think of that may be good ways of understanding a particular disease process. And we're running trials on all these things, by the way. And the gut brain connection is an example of this.

Dr. Koren:
Right. The microbiome is very, very important in determining overall body inflammation. We know that overall body inflammation has a huge impact in a lot of functions, including vascular and brain functions. And that's what we're actually looking at. And sometimes it may seem crazy, but we do clinical trials that prove that that crazy idea actually works.

Michelle:
Well, how do you get involved with a clinical trial if you I mean, people have bad guts. We eat bad food, we're uncomfortable, distressed all the time. How do we determine if it's something more serious, like colorectal cancer or even, you know, something that can be treated over the counter? How do we get involved in a trial that can help move this this forward?

Dr. Koren:
Well, just, you know, on our website, we have a website search dot com called the Anchor Research Group. You can just get on there, Jake's research and you can set an appointment for whatever therapeutic area you may be interested in. Of course, we have great physicians in this community and they're there at the ready to help people understand things, and a lot of us participate in clinical trials as the 100 people here in northeast Florida that are running these studies and participating in clinical trials.

Dr. Koren:
So there are tremendous opportunities. I think our our phone number to calling is 9047300166. And this is that give that number a call and say, hey, I'm worried about my memory and and my gut. Flora, I heard about you. Sign me up.

Michelle:
Well, I mean, but what I mean, I have I have memory and I occasionally have stomach distress. I would I, you know, do I qualify for virtual trial? I don't think so. But I'm just saying, you as a whole, who.

Dr. Koren:
Again, will have people that will screen patients and sometimes they're just what we call the worried well, and a lot of worried. Well, people actually end up in in vaccine studies. For example, we talked about RSV. When we're talking about COVID and RSV is the next virus that we're all concerned about. And we're doing studies as we speak to protect healthy people from that virus.

Dr. Koren:
So there's a lot of opportunities in research here in northeast Florida, and we'd encourage people to give us a call in. And if they're interested in these concepts, I think they'll find that research is a tremendous learning experience. You meet great people like Dr. Changes and other staff members and you're contributing to society because one of the beauties about clinical research is that we learn collectively the information that we derive from you.

Dr. Koren:
It's not shared based on your specific name or we don't identify the patient. But collectively this gets put together and we learn throughout the world from from these experiences. And that's a key difference between research and just being treated by your doctor. Your doctor will do the best that he or she can do to keep you out of trouble.

Dr. Koren:
But we don't collect the information. So the learning that comes from collecting of information is unique to clinical trials.

Michelle:
All right. Well, Dr. Michael Koren ad Dr. Steven, just what final word would you like to say today about our conversation on Alzheimer's disease?

Dr. Toenjes:
I just it's a disease that is affected your family. You personally or your loved ones. You know, there's a whole world of, you know, resources available to you and and part of that world includes the research world and investigate it and and try to move forward as best you can. And there's a lot of a lot of help available.

Dr. Toenjes:
And so I you know, just just trying to figure out what you can because there's a lot of people that can they can do a lot of things to help you.

Dr. Koren:
Amen.