Boomer Living Senior Living Broadcast

Alberto Espay - Alzheimer’s Amyloid Theory Into Question

August 06, 2021 Hanh Brown / Dr. Alberto Espay Season 2 Episode 125
Boomer Living Senior Living Broadcast
Alberto Espay - Alzheimer’s Amyloid Theory Into Question
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Boomer Living Senior Living Broadcast
Alberto Espay - Alzheimer’s Amyloid Theory Into Question
Aug 06, 2021 Season 2 Episode 125
Hanh Brown / Dr. Alberto Espay

Amyloid-Beta And Alzheimer's Disease - Amyloid beta is a protein fragment that's been shown to play an important role in Alzheimer’s disease.

The Amyloid beta-protein is a major component of the plaques that form in many people with Alzheimer's disease. As these proteins clump together, they start to interfere and destroy neurons so research involving this protein has been intense; however, it seems as though there are more questions than answers when it comes to how amyloids cause neurodegeneration.

Alzheimer’s is the most common form of dementia. In 2021, Alzheimer's and other dementias will cost the nation $355 billion. By 2050, these costs could rise as high as $1.1 trillion. - according to alz.org.

If you’re like most people, you believe that amyloid plaques are the cause of Alzheimer’s disease. The amyloid hypothesis is the leading theory for explaining Alzheimer’s disease (AD) and it has been used to develop many drugs that have failed.

The amyloid hypothesis, which states that plaques are causing cognitive impairment, has been the dominant theory for decades. Many scientists have spent their entire careers studying this theory and trying to prove it true. But now there is a growing group of scientists who question if this theory is correct or not.

They found that while plaques do accumulate in the brains of people living with dementia, they aren't actually responsible for cognitive decline.
--------------------

Timestamps:

[00:00] Introduction
[00:02:37] Share with us a little bit about yourself?
[00:03:57] What is so important about amyloid and how does amyloid interact with what we know about the brain?
[00:08:56] How does the structure of this protein differ from other diseases associated with amyloid production?
[00:11:32] Why are we just now discovering that amyloid plaques may be the symptom and not the cause of Alzheimer's?
[00:16:33] What is the timeline like for cognitive progression for amyloid protein deposits?
[00:21:53] Does this research mean that we will see any human trials in the future?
[00:26:49] Do you recommend that people start to monitor their amyloid levels early like today, just in case they have early signs of memory loss?
[00:31:53] Have you noticed cognitive improvements after being treated with drugs that lower amyloid levels?
[00:35:11] Let's say if this theory is correct, what do you think the implications are for Alzheimer's patients and their families?
[00:37:33] Did any of these studies mention what genetic factors or risk factors might be tied to?
[00:39:51] Is there a link between gut health and Alzheimer's disease?
[00:41:58] Do you think that there are ways for people with a family history of Alzheimer's disease to reduce their risk?
[00:52:15] Do you have anything else that you would like to share?
[00:53:08] How do people reach out to you?
--------------------

Bio:

Dr. Alberto J. Espay is a Professor and the endowed chair of the University of Cincinnati James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders. His research efforts have focused on the measurement of motor and behavioral phenomena in—and clinical trials for—Parkinson’s disease as well as in the understanding and management of functional movement disorders. Recently, he launched a phenotype-agnostic biomarker development program for neurodegenerative diseases with the aim to identify those small but biologically suitable subgroups most likely to respond to therapies already available or under current investigation.

Learn more about Alberto:
LinkedIn: https://www.linkedin.com/in/alberto-espay-9a834758/
Website: https://www.uchealth.com/physician/alberto-espay/
----------

Show Notes Transcript

Amyloid-Beta And Alzheimer's Disease - Amyloid beta is a protein fragment that's been shown to play an important role in Alzheimer’s disease.

The Amyloid beta-protein is a major component of the plaques that form in many people with Alzheimer's disease. As these proteins clump together, they start to interfere and destroy neurons so research involving this protein has been intense; however, it seems as though there are more questions than answers when it comes to how amyloids cause neurodegeneration.

Alzheimer’s is the most common form of dementia. In 2021, Alzheimer's and other dementias will cost the nation $355 billion. By 2050, these costs could rise as high as $1.1 trillion. - according to alz.org.

If you’re like most people, you believe that amyloid plaques are the cause of Alzheimer’s disease. The amyloid hypothesis is the leading theory for explaining Alzheimer’s disease (AD) and it has been used to develop many drugs that have failed.

The amyloid hypothesis, which states that plaques are causing cognitive impairment, has been the dominant theory for decades. Many scientists have spent their entire careers studying this theory and trying to prove it true. But now there is a growing group of scientists who question if this theory is correct or not.

They found that while plaques do accumulate in the brains of people living with dementia, they aren't actually responsible for cognitive decline.
--------------------

Timestamps:

[00:00] Introduction
[00:02:37] Share with us a little bit about yourself?
[00:03:57] What is so important about amyloid and how does amyloid interact with what we know about the brain?
[00:08:56] How does the structure of this protein differ from other diseases associated with amyloid production?
[00:11:32] Why are we just now discovering that amyloid plaques may be the symptom and not the cause of Alzheimer's?
[00:16:33] What is the timeline like for cognitive progression for amyloid protein deposits?
[00:21:53] Does this research mean that we will see any human trials in the future?
[00:26:49] Do you recommend that people start to monitor their amyloid levels early like today, just in case they have early signs of memory loss?
[00:31:53] Have you noticed cognitive improvements after being treated with drugs that lower amyloid levels?
[00:35:11] Let's say if this theory is correct, what do you think the implications are for Alzheimer's patients and their families?
[00:37:33] Did any of these studies mention what genetic factors or risk factors might be tied to?
[00:39:51] Is there a link between gut health and Alzheimer's disease?
[00:41:58] Do you think that there are ways for people with a family history of Alzheimer's disease to reduce their risk?
[00:52:15] Do you have anything else that you would like to share?
[00:53:08] How do people reach out to you?
--------------------

Bio:

Dr. Alberto J. Espay is a Professor and the endowed chair of the University of Cincinnati James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders. His research efforts have focused on the measurement of motor and behavioral phenomena in—and clinical trials for—Parkinson’s disease as well as in the understanding and management of functional movement disorders. Recently, he launched a phenotype-agnostic biomarker development program for neurodegenerative diseases with the aim to identify those small but biologically suitable subgroups most likely to respond to therapies already available or under current investigation.

Learn more about Alberto:
LinkedIn: https://www.linkedin.com/in/alberto-espay-9a834758/
Website: https://www.uchealth.com/physician/alberto-espay/
----------

Hanh:

Hi, I'm Hanh, Hanh Brown. And thank you for tuning in. This conversation is live streaming and all the various social media platforms. We are all about older adults. It's time to bring on the wisdom and perspective of those who have mastered life. So please check us out on our newly named YouTube channel Aging Media Show. This is where I will put all of my video podcast recordings from Boomer Living. Also, I will share topics and digital health, senior housing, senior living, and aging in place to help you understand what is happening in our world, as we age. We will also be talking about strategies for caring for older adults and tips on how to live a healthy life. On this platform I will feature guests appearances by experts to share how technology is changing our lives and what it means for society and how long-term memory loss affects everybody, our parents and grandparents. So visit us on our newly named YouTube channel Aging Media Show. Today my guest is Dr. Alberto Espay. Dr. Alberto Espay is a professor of medicine, neurology at the University of Cincinnati. He's the chair of sections in the American Academy of Neurology. Alzheimer's is the most common form of dementia, and in 2021 Alzheimers and other dementia's will cost the nation $355 billion. And by 2050, these costs could rise as high as $1.1 trillion, according to the alz.org. If you're like most people, you believe that amyloid plaques are the cause of Alzheimer's disease. The amyloid hypothesis is a leading theory or explaining Alzheimer's disease, and it has been used to develop many drugs that have failed. The amyloid hypothesis, which states that plaques are causing cognitive impairment has been the dominant theory for decades. And many scientists have spent their entire careers studying this theory and trying to prove it true. But now there is a growing group of scientists who question, if this theory is correct or not. They found that while plaques do accumulate in the brains of people living with dementia, they aren't actually responsible for the cognitive decline. So Dr. Alberto is here to share this findings. So Dr. Alberto welcome.

Alberto:

Thank you very much, Hanh. I'm delighted to be with you.

Hanh:

Great. So aside from your professional profile, can you share with us a little bit about yourself?

Alberto:

Absolutely. I am a movement disorder neurologist. I finished my neurology training at Indiana University. And to become a movement disorder in neurology. I went to Toronto, University of Toronto. Now movement disorders is a field that encompasses neural degenerative disorders. And that includes, of course Parkinson's, Alzheimer's, and other conditions as we have classified them. I have been in Cincinnati, at the university of Cincinnati since 2005. And we have a large program for people with due to degenerative conditions. And one we're very excited about relates to the idea that everyone is different and that this is the first program that will in fact, identify individuals for the biology that got to the disease they have rather than for the way they appear to our eyes and the way they appear on examination. I'm happy to discuss that, but I'm delighted that you introduced the topic of amyloid which has been a, an area of great deal of interest to us, for sure.

Hanh:

Great. Well, thank you for being here. So let's bring everyone on the same page. What is so important about amyloid and how does amyloid interact with what we know about the brain?

Alberto:

Absolutely. Well, the first thing to recognize is that amyloid beta is a normal protein, we all have. It is incredibly important for many functions that relate to the growth of neurons, to the comunication between neurons to the sustanance of neurons. It's just one of the most important proteins our brains have. And what happens is when the brain is dealing with biological toxic or infectious stressors, these amyloid beta as a reactive mechanism, ends up clumping together. It's a matter of offending off these aggressors to the brain. That process of aggregation is irreversible. So it really is not a process that can be turned back. It's a process that follows a thermal dynamics which is lots of physics. And the physics are that proteins that are soluble in their normal state, meaning they are liquid. That's the way that they can operate. They clump together and become solid. And so the transformation that happen is from functional to non-functional. Now amyloids are conceived as being toxic, and that is a leap of faith that we jumped in a little too fast and have never been able to prove it. I can show you, I don't know if you want me to do a little demo. So I'm going to use, I have this is a kleenex box and this is of course a one sheet, and I like this as a link through the amyloid beta, because I'm going to beta is in a very fluid state. So it really kind of goes like this. But as I mentioned, if brain has something that shouldn't be there, let's say a viral infection. In fact, herpes simplex virus is a cost of something that we currently think of as indistinguishable from Alzheimer's. This is a virus, for instance, then what happens with these proteins on exposures is this, it adopts a configuration called beta-sheet, that is so stable, it makes it, irreversible. But it's also so stable, it's super hard for it to be toxic. It is the equivalent of a little tiny stone that's developed. Now, why we've been thinking of this as a toxic is cause because our concepts of Alzheimer's were based on autopsy studies. And in autopsy studies that this has gone and this is all we see sprinkled throughout the brain. This is not normal. And so we say, gosh, this is probably the cause of the problem. And that's how we started saying, if we can get rid of this we'll be great, we'll bring brain to health. And it has been done to well the latest medication was the first to be approved by the FDA to do this. In fact actually is not the first to do this. There are 17 other drugs that did the exact same thing. It cleaned this beautifully from the brain, but people either did not change, or got worse. And in fact, many of the studies have shown that the most success we have with reducing the amyloid, the greater, the greater, the atrophy of the brain, the brain shrinks. So it's not that we need to get rid of this, but rather we're now finding that we need to replace which, which we are losing. So we're losing this in the process of it becoming aggregates. So this is the consequence of the problem. The cause of the problem is invisible to most of us. We don't know what, what really creates the problem to begin with. But one way to compensate, won't be to try to insist getting rid of this, but rather to at least begin the process of replenishing the proteins that work. We're losing.

Hanh:

So, how does the structure of this protein differ from other diseases associated with amyloid production?

Alberto:

So these protein is actually a bunch of amino acids coming together. These are the unique structures, but they have to be able to operate in three dimensional space. And that's why this is in this way it is largely fluid it's liquid. All proteins in the brain that are functioning are in their soluble state. And when they accrue a conformation called amyloid, this is the amyloid is a state of the protein. Once they become amyloids, they are no longer functioning. So the certainty is that proteins can only function when they are in their normal liquid or soluble, we call it state. The minute they are in a different state, they can no longer function. So a certainty in biology is that we lose function as the proteins transforming to amyloid. But what we've embraced is the uncertainty that as they accumulate in this fashion, they become toxic. We've overlooked this certainty and completely embraced the uncertainty and the more data we've had about the way we're dealing with the uncertainty, the more we recognize it is the incorrect approach because it is not bringing patients back to brain health. It is letting them be just the same, but quite often rendering them worse. And this is why this drug that was approved is so controversial because the FDA could not say that the drug was effective. It could only say that the drug reduced amyloid and the expectation is that in the future, that could be good. But even within the time window of clinical trials, we know that patients aren't getting better or are getting worse. And therefore there is no way that they can expect a future where reducing this might in any way be translated into a future in which they will actually be better.

Hanh:

So now why are we just now discovering that amyloid plaques may be the symptom and not the cause of Alzheimer's? So, I mean, you share some thoughts. But what does that say on this new study? That we might be viewing dementia incorrectly. And what does this mean? Going forward for public health research and clinical medicine treatments?

Alberto:

So, let me tell you then what we did, because that's a great question, and it was the reason why we studied these in detail. So they broke that, the straw that broke the camel's back, I should say was that in the largest study that the Mayo Clinic study did, they, it's a population-based study, they demonstrated that we accrue amyloid for, forever. We are, as we age, the more we age, the more amyloid we accumulate. In fact, by the age of 60 about 15% of us have amyloid in our brains by the age of 85, 60% of us have amyloid.. So most of us will have amyloid in our brains. Now that's the curveof amyloid, it goes up as we age. The narrative is, that means we began the process of Alzheimer's. It's an interesting narrative, but it's entirely false because the other curve to look at is what happens to individual's cognition, and overall function? It's actually flat throughout most of the first 15, 20 years, and at the age of 85, which is beyond a normal life span, at least in the United States, it's when he begins to start looking parallel to the curve of amyloid increase. If amyloid were really the problem, you would expect that the curve of amyloid increase and the curve of dementia will begin to approach one to the other. So the ratio between the two be would close to one within a normal lifespan, that's not what happened. So what do we do to ask the question you just posed? We said, well, because most of us that have amyloid did not have dementia. We asked the question of every individual without amyloid in the brain already participating in the Adney study, which is the largest study that has been done to understand biomarkers for Alzheimer's is now running for almost 20 years. So we took all 600 individuals that already have amyloid, many of them, of course have normal cognition. They were doing fine. Some had mild cognitive impairment and some have dementia. We asked a question, is it possible that the reason you can be cognitively normal is because you are still able to keep levels of this soluble fraction above level of compensation, that the difference between those who are cognitively normal versus those who have dementia, even though everyone has equal levels of amyloid in the brain is because they are able to sustain the levels of this soluble normal fraction of the protein. And that is exactly what we found, that it didn't matter how high the levels of brain amyloid got. It didn't matter how much of this got. It, the only difference that was able to be determined between those who have normal cognition and dementia was how much higher, the levels of soluble, where in the brain of the amyloid positive individuals. So that explained the paradox that we have dealt with for so long, which is, gosh, you get amyloid and sure there is a correlation. If you ultimately develop dementia, yeah, you have amyloid. But why is it that the correlation is so poor, the older we become? Why is it that among centenarians, half of them have amyloid and they are normal? And half of them have dementia and have no amyloid, it's something else happening with them. So once we deal with centenarians, the data is mind blowing. It destroys the way in which we have conceived Alzheimer's because it no longer, amyloid no longer means what we think it means. And now this study explains why that is. It finally gives sense to the idea that amyloid is just the end of the process. And if the beginning can be somehow harnessed to some extent that patients can still rev up the levels of producing their normal protein, they can have a lot of amyloid, but they are going to remain cognitively normal.

Hanh:

Wow. Okay. So, what is the timeline like for cognitive progression for amyloid protein deposits? What does that look like?

Alberto:

So the answer is we don't actually know how long it might take for somebody that accumulates amyloid to ever, if you've ever develop dementia, it may be that it's never going to happen. In fact I've mentioned to you the age of 85, cause it's an interesting age. By the age of 85, I told you, 60% of us we'll have amyloid. Only 10% of us will have developed dementia. So there is a five fold, lower prevalence of dementia by the age of 85, than would have been expected on the basis of the presence of amyloid. That is a great indictment. And in fact, this was done in 2019 and the authors of that very important paper noted, this is confusing with me, this creates a problem with understanding the concepts that we know very well and but it's important to explain that this is kind of like cholesterol they'd like to use the idea that this is kind of like cholesterol. You just have something bad and you need to act on it the same way and how do we explain this? We can not, but interestingly we already have evidence of individuals who are normal and have a mutation in a gene that gets them to have more amyloid, right. And have already given them anti-amyloid therapy very similar to Aducanumab, the medication was recently approved, great success in reducing their amyloid. And what happened to those individuals? Well, only those treated with placebo continue to be normal. Those given anti-amyloid treatments was they began to develop cognitive symptoms and in some cases their brain begins to shrink. So even in what would be conceived of perfect type of individual in whom to try to clean off the amyloid. Just people with our symptoms, right. Are supposedly at risk because they already have amyloid and they have a increase of amyloid that they will be the ones we would intervene because then we will stop the development of the dementia. In fact we are creating the beginnings of the dementia by starting to clean off the amyloid.

Hanh:

Wow.

Alberto:

It really is. It's a, it's something that I think we need to move away from, and the reason I like our conversation Hanh is because to be frank, we neurologists are very comfortable keeping things the exact same way we've done for decades. We're just creatures of habit. We are very respectful of our traditions. We think our forebears were giants in that we are going to validate each of them because back in the 18th century, when our definitions for diseases began to appear, they were not out to just define the diseases but they were certainly telling us something about the molecular biological constructs behind diseases, and they were not. So we're, what we call Alzheimer's disease, biology has no idea what we mean. No idea. There is no boundary specific around this concept of Alzheimer's we've created. It makes sense to us. It's logical. So Hanh I think that it will be up to patients and advocates to say, you guys need to change your approach because you aren't getting any better by trying to do the same approach, time and again. It is the definition of insanity, according to some, trying to keep on doing the same thing and expected that one day we would have it, we would strike success. We aren't. And in fact, because were so adamantly convinced that we are on the right track is what we, why we ended, ended with Aducanumab. The approval was this idea that patients and patient advocates were saying something is better than nothing. And that's why we have this program but if you look at the datas, this something is worse than nothing. If nothing is placebo, half of the pictures in the clinical trials on placebo did better than those on the medication. Placebo was better, so therefore this is worse than nothing.

Hanh:

Yeah. I mean, when you say something is better than nothing, I look at that as long as something is not regarded as accepted or approved, because there's plenty of somethings out there as long as it's in, in motion in clinical studies and so forth, that's all good. But when something is accepted, FDA approved, that creates a trust issue, right?

Alberto:

Absolutely.

Hanh:

It comes with regard, regard that perhaps is in question. So we'll, we'll cover Aducanumab later on. So I wanna ask you, so does this research mean that we will see any human trials in the future?

Alberto:

Yes. We will the study that we now are the studies we're now working on relate to accruing as much safety, and potential efficacy in animal models. So we're now doing rescue therapy in animals. In fact, that's what we're beginning to see that not unexpectedly when you have an animal model that has a depletion of the normal protein because he has too much of this already there. And if you increase those levels, you, we're seeing rescue both at the cellular level as well as at the behavioral levels, you can see improvements in animals. Now the process of replacement therapy will be coming to humans, it's what other fields of medicine have done insolin, what is a replacement therapy that recently turned a hundred years old. And so it's a great model to understanding. Most of the problems we have our problems of insufficient proteins not of too much protein. So we replaced the insolin protein. Here we should be replacing the amyloid beta protein, right. We've been focusing on this, on the complete opposite angle and not taking the answers we've receive as indictments on our ideas, but rather on indictments on the trials. We think our ideas are perfect, but it is the darn imperfect trials that have not been able to tell us that, which we all along have known to be the truth. So we think that we are probably three or four years up from the first in human trials of soluble replacement, but this will be the first demonstration, we think of an approach to replace a protein in a neurodegenerative condition. Alzheimer's will be likely the first that would then help patients to sustain the levels or in people who are cognitively normal in fact remain cognitively normal. So these would be what we would call rescue therapy. It's not by precision medicine. And I can talk later if you wish about the difference between the two, but rescue is very important because even if we don't know what the, what is causing the brain to churn that much amyloid, we could at least keep the levels of the normal functioning protein above the level of compensation. And patients can do very, very well. We have to prove that, but the evidence indirectly from what we've done and from the study that I've reported to you recently published, suggests that that is really the most sensible strategy. Almost, almost too simple to think that this is taken us so long to come to the conclusion that the problem here is the brain is losing proteins. One analogy that you might find interesting that I have come to use to explain how we think about Alzheimer's. If you, do remember Alzheimer's is defined by the amyloid in ag in the patient's aggregate, right? Well, in an amyloid pet imaging, that image is that of a lot of red. When you see a lot of red, that's telling you the brain is filled with amyloid. That's bad we say, right. Well, that's the same, eh, that's the same approach of a map of deforestation. If you see a property of deforestation that is green in the background, but a lot of red in the foreground, and we never think on a deforestation map that the problem is are those chopped up trees? We never say, gosh, if we just cleaned the chopped up trees, all the debris that forest will come back to normal. Now we know that the forest can only come back to normal by reforestation. Why is it that we don't think in the same manner when we looked at the pet? We see all this red stuff and we never say this is we're losing brain. We never think about losing brain, which is gaining toxing, a toxic thing this amyloid, so toxic. And so in many ways it's coming back to the basics. If you looked at it, there's just that the brain is losing something and it's accumulated into what you could think of as just the debris of its former self. In fact, some individuals think amyloid is a tombstone of the normal protein. Tombstones can really not do much of anything. The problem is we've lost the protein in the normal state.

Hanh:

Wow. So, all of those is in motion and I guess do you recommend that people start to monitor their amyloid levels early like today, just in case they have early signs of memory loss?

Alberto:

Right? No, I don't. I don't think so. And I, perhaps the key message to people here is to stop fearing amyloid. Amyloid is not an enemy. Amyloid is not the central villain in the drama of neurodegeneration. Amyloid is not a cost of the problems. Amyloid is a sign that the brain is fighting against something. And for the most part of the brain is fighting quite successfully. Amyloid, in fact, is needed for many of, the formation of amyloid is needed as the brain reacts against stressors against the invaders, against poisons that's what happens. The brain really clumps up quite a bit. And sometimes when they injury passes, then, then amyloid goes back to where it was. The amyloid that is formed is gone, but the brain continues to develop the proteins and then it continues to function normally. Actually one example of this, I have to tell you is a great is a great example of how we think. So if individuals that are normal, having a amyloid pet also is normal, no amyloid, right? If they are asked to not sleep one night, only one night and the very, and also a sleep deprivation means not maybe a few hours as possible, right. And the very next day we ask them to undergo another pet scan. What's going to happen is that it will be abnormal. There'll be amyloid in the brains. So what's interesting about this is that if you looked at how that was reported is that sleep deprivation is a cost of Alzheimer's. And it kind of rings a familiar tone. We all know that people with Alzheimer's have problems, so it kind of makes sense. Maybe it's they generated the Alzheimer's or it kind of makes sense. But with this same data set, you can always say the same, the exact opposite. You can say the brain reacted against the injury of sleep deprivation by protecting itself with amyloid. The amyloid was a reaction, to the injury. And so why do we know? Well, because when, once these individuals start sleeping again, the amyloid goes away. So it's not that that began, that's the beginning of Alzheimer's. This is just that we, our brains undergo a variety of injuries through our life, sleep deprivation, all of us go through it. And that means that all of us have had amyloid developed in our brains because of a bad night of sleep. It doesn't mean that's when we began to develop Alzheimer's at all, it just is a sign that the brain is reacting against something. That we have taken it out to meaning the cause of the problem is because we've conflated correlation with causation and that's a violation of science 101 unfortunately. Yeah. So basically there is no clear proven definitive correlation. It was just what's the right word? Just formulated and everyone follows suit. Exactly. And so once we have a theory that we elevate to dogma, no evidence can, can demote it. The amyloid hypothesis is really not a hypothesis. It's a dogma because hypothesis are scientific ideas that can be falsified. If we cannot falsify a scientific idea, no matter how much evidence to the contrary there is that isn't a scientific idea. That's dogma. And so the dogma of amyloid has permeated everything. That's why the FDA approved this drug because the FDA thinks that lowering amyloid is the way to go because all of us think that way. It's it's a normal reaction you say, but this drugs is so good because it does exactly what the, what we want the drug to do, because amyloid is the enemy. So that's that's so that's, that's a belief that's so strong that evidence cannot compete against. And that's something we need to break away from. And I think that patient and patient advocacy groups are perhaps a key to really ensuring that there will be a change because as I mentioned earlier. We we're very comfortable doing the same. I think we're continue doing the same for as long as we can. It's easier not to change.

Hanh:

I'm just thinking out loud. Perhaps the Aducanumab FDA approved, just satisfied a need where people were looking for hope promise something to hold onto maybe, but I guess as a result, I'm not sure if it met that purpose, right? Because there's a lot of mistrust. So it's it's interesting. So now, have you noticed cognitive improvements after being treated with drugs that lower amyloid levels?

Alberto:

yes it, well, I cannot offer it to any of my patients, any of those trials, but the data from those trials is quite remarkable, quite remarkable. I just recently published a summary of all 40 clinical trials of anti-amyloid treatments. Forty, you would think what other field of medicine continues to do the same thing and again, and continues to doing it because they think that the next trial will be the one that tells us the answer we've all along, been expecting. No other field of medicine gets away with this. We do because of the power of hope. I would argue the power of blind hope, unfortunately. So, yes in so, so amyloid reduction has been accomplished in about 75% of all trials. So actually great success mean that most drugs created lowering amyloid have lowered amyloid. They have lowered so well that almost half of all studies have shown the patients have gotten worse. So when we think of the history of the trials, most of us think, oh, well the trials were negative because maybe there weren't enough patients. Maybe the measurements weren't sensitive enough. A favorite one is maybe the patients were too advanced, right? No, the studies were positive, if we think of what is it that we wanted to accomplish to lower amyloid. It just so happens that the many, many patients worsened. And so there is utility. Yes. In about half of the studies.. But half of the studies shown that the patients are worse compared to placebo. The placebo treated patients were better than those who had a active intervention that successfully reduced the amyloid. But we know that. The evidence is there. And that's why when I some colleagues say, well, you know what? Now that the FDA approved Aducanumab, let's do phase four study because that will be that, that will give us the answer. And as a phase four studies, we'll never have the rigor of phase three. If the phase three data cannot tell you the answer you're seeking. Why would we expect that the one phase four study somehow will tell us exactly that which was elusive to the far more rigorous phase three trials?

Hanh:

Yeah. So let's say if this theory is correct, what do you think the implications are for Alzheimer's patients and their families?

Alberto:

I think that the expectation is that now we can see a path forward for true improvement, that the, that if we changed the language, if we stop calling amyloid the villain. If we spoke calling the diseases proteinopathies. Proteinopathies are the term used, right? Amyloidopathies for Alzheimer's. Synucleinopathies for Parkinson's. Tauopathies for progressive supranuclear palsy. We have opathies for many of these conditions. Proteinopathy means the protein has gone rogue. It has become terrible. It's deceased. No, the protein is acting as a protein, the proteins simply polymerized, and lose their function. They become amyloids. So proteins have functions in loose functions, right? So if we can change that now, then we can see things for what they are. If it's a matter of just saying, gosh, now with a promise here, two people is a weekening fact, rescue the brain by adding that which the brain is depleting. And that's why the correct term is not proteinopathy, but proteinopenia. Proteinopenia means a reduction in the level of proteins. And it's well-established that in people who have Alzheimer's disease, amyloid beta is really low in the spinal fluid, which is where we can capture the soluble normal fraction of the protein. But we've just been paying to that, which is the aggregated form, right. So the, I consider these new research, highly promising. I think this is the most exciting, most truly innovative. And the one with the highest likelihood of succeeding, because it only makes sense as opposed to digging into our beliefs. It's actually data showing us that no matter how much amyloid we have, if the levels of amyloid beta are high, we won't have dementia. So to me, that is incredibly exciting.

Hanh:

Mm Hmm. Mm Hmm. Now, did any of these studies mention what genetic factors or risk factors might be tied to?

Alberto:

So there are many well there are at least three very important genetic factors that made the protein inherently unstable and therefore rapidly becoming amyloids. There are, those are three genes APP's, one, and the other ones are called presenilin's. Presenilin one and two. So those three ended up creating instability of the protein. And this protein becomes quickly like this without the need for anything to in fact, trigger that aggregation. So in those patients, the same approach would work just the same. You would want to give them as much of the soluble to, prevent them to evolving into dementia because they, the risk in them is higher, of course. It's just remarkable that we've had now three trials in individuals with amyloid do to genetic mutations. And all 300% have been negative and negative in the true sense that those treated did worse compared to those not treated, given placebo. So, yeah, so the genetics that we have used, it's interesting because the genetic forms of Alzheimer's, are conceived as the reason why amyloid is bad because there's over expression of amyloid that, and that causes the disease is not the overexpression of amyloid it's the overexpression of the depletion of the normal protein becoming amyloid. And so you're still loosing protein. So the idea I hope of proteinopenia, the loss of function, it makes a lot more sense, and it's easier to correct than the gain of function. These very complicated treatments that do remove amyloid, but do so at great cost to the brain. In fact, 40% of patients in the Aducanumab trials developed brain swelling, or other abnormalities of the brain. So it's not trivial doing this at all.

Hanh:

Wow. Now, is there a link between gut health and Alzheimer's disease?

Alberto:

Eh, conceivably the so-called gut brain axis is one that is telling us that there probably is a big connection between our environment and our brains. And the environment, as far as what we consume ends up generating the type of bacterial populations that live within us, the so-called microbiome and the short answer is we don't yet know what about the microbiome is good and what is bad for the brain specifically as it relates to the types of microbial species. We don't know that. But we suspect that there is a correlation. Now, what we know is that the healthiest microbiome is the most diverse meaning the more variety of microbial species you have, the better. And I think that's accomplished through a well-balanced diet. If your diet is restricted, or if it's heavily dependent on processed carbohydrates, the diversity of your microbiome is small and that is a diseased microbiome. It probably will have detrimental effects on the brain. So I think for now that's where we are. And eventually maybe that once we reach a level of sophistication where we can understand the effects of an individual's microbiome on that person, we might be able to manipulate the. The concentrations of each of his through a variety of different methods, but dietary intervention, probably the most effective to rev up certain populations that are more conceivably favorable for that individual and rev down those that may in fact, cause some difficulties.

Hanh:

Do you think that there are ways for people with a family history of Alzheimer's disease to reduce their risk?

Alberto:

I think so. I think that the risk that they have either genetic or otherwise is, it's a mod is, it can be modified. There are lifestyle choices we've all make that can make that risk greater or lower. In fact even if you have a gene that would make that risk very high. You might have it and never developed the disease if you are active. If you have an exercise programs that includes an aerobic component. So a cardiovascular element, you sweat and pant elevate your, your your heart rate and then combine it with stretching and weight lifting. And if you can do that for literally as little as half an hour, three times a week, you get the benefits of what no medication can which is a neural protection. You are neural protecting your neurons. Exercise yields, all sorts of interesting biological elements and among them are neuron growth factors. So these are sort of the fertilizers for the brain that are generated through the work of exercise. We talked about diet. The Mediterranean diet is out of all the diets, perhaps the most studied and ostensively effective. And in fact, this may be a reason why Mediterranean populations, the rate of Alzheimer's and Parkinson's and other neurodegenerative diseases is lower, and the lifespan longer. Red wine happens to be good for the brain. That's part of the Mediterranean diet. So that's very helpful. And then coffee, coffee turns out to have all, many benefits. So coffea in the mornings, red wine in the evenings. And a mediterranean diet through the day with the good regimen of exercise. We see this, we see that families of individuals with a genetic condition that would render more vulnerable to developing Alzheimer's, those who decide that they're going to take action, because of the risk they know and apply these principles of lifestyle changes. Boy, they do well. They do really well. And some of them don't have, don't develop the condition that they would have in the past been considered to be unavoidable. Even a gene is not prescriptive in the past, we used to think gene tells you what's going to happen. No, a gene is just a bit of a template, but he can be changed by what you do.

Hanh:

So, it sounds like lifestyle choices, more heavily weighted as opposed to it runs in the family.

Alberto:

Exactly. Exactly. That's absolutely true. That that's is ultimately the case. Every one of us has a lot more power in ourselves than perhaps we are aware off, and that power can be put to good use. There isn't anything prescriptive about the family history. Yes, there can be a family history heavy over anything, but you can buck that trend based on what you, on, what you do. That's so important. And by the way, I, as I'm talking about and thinking about these issues, another aspect that I think is one, we physicians cannot measure well, is the extent to which you think positively or whether you're a pessimist. Now, that's a personality trait, I think for most of us, but you can probably change a little bit here. But the reason I'm pointing this out is because in my years of being a neurologist for so many people I used to think back when I well this shortly yeah newly minted neurologist that I kinda knew what the prognosis was for everyone, right. Now, I've done so much of this, that I actually don't know what is in the future for anyone. But back when I thought I knew there are certain guidelines where we can tell if a person is going to do well or do poorly. And I remember, this wasn't now, this was one of my first patients in Cincinnati, 2005. I saw this woman who I thought everything I knew suggest that she had maybe two years to live, at most. And she didn't believe it. In fact, she's like ah, I have so much that I have to do. I have things I have to do for my kids and my grandchildren, and I can, I can, essentially, he was telling me I can bother with this. I have just too much on my plate. I have a lot of things to do. That person is still alive and kicking. Is still alive and kicking. And we're talking about 2005 when I say, oh, 2007. So she has taught me humility about what I thought I knew, but also the power of all of us in the way we think. We ultimately are self-fulfilling prophecies. We become what we think we will turn into what we are, who we think we are. And so, unfortunately that applies the other way too. People who, everything points in the direction that they're good. But if they receive a diagnosis such as Alzheimer's or Parkinson's,

Hanh:

Life is over.

Alberto:

life is over. And they end up proving themselves right. There's nothing that should move in that direction. So there is that power, we don't know how to measure it. We know it's there, it must be biological because it clearly changes. So that aspect, I wish we could somehow harness. But I don't know how, but it's, it's, that's so important. And that goes to the theme of having so much power within us. We can in fact, change the destiny that perhaps we think is unavoidable by virtue of our family history.

Hanh:

Mm Hmm. You described the woman that you thought had two years? It sounds like she had purpose, right? She has purpose and spending time with her children, grandchildren and the excitement and the drive and the happiness that she has every day with purpose with her family and beyond that's huge. And, how do we instill that in individuals, right? It's a self driven, not given, but it's self driven.

Alberto:

It requires an effort for sure. It has to be deliberate. It won't come by itself. If one appear out of the blue. It requires, I think you'd request a little bit of faking too. The whole fake until you making it is I think there is a lot of truth to it. At some point you fake it so much. You don't know if you're faking it anymore, right? Because at some point it looks like that's what you are doing and thinking. So maybe if it doesn't feel right you just fake it for a little while. And eventually it becomes what you would you, when you think and what you are motivated in doing. How many of us even know that when we begin our exercise, we will rather be doing something else? We just push ourselves. We just do it because we know it's important. Eventually. We're so happy we did it. So nothing that is worth our while is easy. If things were too easy, they were not probably be worth doing, as we all know. So yeah, I think that will be a very important message. And maybe the most important of them all to know that patients have in them more power than any of the medications we can ever conceive for them. And I don't think there'll be a pharmaceutical company that could ever replicate the value of what someone's expectations of the future are. It's just, just too important and too powerful to ever be matched by any medication.

Hanh:

What you're describing is ownership of your health and your lifestyle. And that happens as early as you can. As young as you can. Not when your sixties, seventies, and so forth. It all accumulates, right?

Alberto:

Absolutely. But it's never too late to change. Sometimes some of us are in activities that or lack of activities the we've set ourselves forever. And so when something such as a diagnosis of Alzheimer's appears in the horizon, it's actually a time to change things for the better. It's time to rev activities. It's increasing the engagement socially, intellectually even if you don't feel like it. Even if going out doesn't feel like it's what you want to, do it. Even if going to the gym is something that you rather not, do it. Don't do it because it's easy. Obviously you're doing it because it's hard, but because it's important and it'll make a difference. So I have had patients that have never exercised in their lives, never, and they're, they're doing it now and they feel, gosh, I should have done this much earlier I feel so much better. And sometimes some of them have said, yeah, I feel them so, so good. I know I have a disease. I would rather not, but because I'm exercising, I feel better. So it's very empowering and that's all free. There is no charge for that, right? That's all that you can dig from within yourself.

Hanh:

That's true. That's true. Well, I really appreciate your time. Gosh, thank you so much. Do you have anything else that you would like to share?

Alberto:

I just hope that our, everyone listening to you looks at the new medication for Alzheimer's with big deal of skepticism. The FDA approval is not an endorsement of the science. It's an endorsement of our hopes. And I hope that no one will be harmed with this drug. I cannot give it to anyone, but I, it's important that we all are all educated in avoiding the risks that come from something that has no potential to helping us and much to harm us. And with that, I thank you very much, Hanh. You've been great to have a conversation with, and I hope all of your fan club will be delighted with this conversation. I'm happy to entertain any questions via email or any other method. I'm delighted to keep the conversation going.

Hanh:

Absolutely. And how do people reach out to you?

Alberto:

The best way is via email. I'm very responsive to my emails. My email is alberto.espay. So it's my first name dot last name @uc.edu. UC stands for University of Cincinnati. Yeah.

Hanh:

Great. Well, thank you so much. Until next time.

Alberto:

Thank you so much.

Hanh:

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