Imagine for a moment that you are watching your loved one slowly deteriorate.
They can no longer remember your name, what they did yesterday, what to do with their keys, or even how to brush their teeth. As the disease progresses, they become more and more withdrawn, until eventually, they can no longer recognize the faces of their loved ones. It's a heart-wrenching experience that I wouldn't wish on anyone.
This is the reality for millions of people around the world who are affected by Alzheimer's disease. While there is no cure for Alzheimer's, there is hope. New research is providing insights into how we can better treat the disease.
One such study has found that targeting amyloid beta could be more effective than previously thought.
Amyloid-positive carriers of autosomal dominant Alzheimer’s disease-causing mutations were put under observation for 3 years.
The study found that higher levels of soluble Aβ42 predicted a lower risk of progression to cognitive impairment to a greater extent than lower levels of brain amyloid. In other words, it showed that treating Alzheimer's disease by targeting amyloid beta could be more effective than previously thought.
This is an important finding that could change the way we approach Alzheimer's disease treatment in the future.
For me, these hits close to home. My mother, mother-in-law, my brother-in-law, neighbor, sister's mother-in-law, and I have watched as the disease slowly robbed families of their memories, their ability to communicate, and eventually their mobility.
To see that there might be a way to target the disease more effectively is very exciting. It gives me hope that one day we might be able to slow down or even stop the progression of Alzheimer’s and Give people like me and your loved ones some of their precious memories back.
Today my guest is Dr. Alberto Espay. Alberto Espay is a professor and endowed chair at the University of Cincinnati's James J. and Joan A. Gardner Center for Parkinson’s disease.
He has published over 300 peer-reviewed research articles and 8 books, including Common Movement Disorders Pitfalls and Brain Fables: The Hidden History of Neurodegenerative Diseases and a Blueprint to Conquer Them.
Espay has served as Chair of the Movement Disorders Section of the American Academy of Neurology, Associate Editor of the Movement Disorders journal, and on the Executive Committee of the Parkinson Study Group. He recently launched the first biomarker study of aging (CCBPstudy.com).
You can reach Alberto via these channels:
Hanh Brown: Hi, I'm Hanh Brown, the host of the Boomer Living Broadcast. On the show, we discuss in-depth topics that are relevant to baby boomers. We identify challenges and opportunities so that we can better serve this generation. Today's topic is "the study finds that Amyloid Beta 42 loss of function is a key factor in the development of Alzheimer's disease."
Hanh Brown: Imagine for a moment that you are watching your loved one slowly deteriorate. They can no longer remember your name, what they did yesterday, where they put their keys, or even how to brush their teeth.
Hanh Brown: As the disease progresses, they become more and more withdrawn until eventually, they can no longer recognize the faces of their loved ones. It's a heart-wrenching experience that I wouldn't wish on anyone. This is a reality for millions of people around the world who are affected by Alzheimer's disease.
Hanh Brown: While there's no cure for Alzheimer's, there is hope. New research is providing insight into how we can better treat the disease. One such study has found that targeting amyloid beta could be more effective than previously thought.
Hanh Brown: Amyloid positive carriers of autosomal dominant Alzheimer's disease-causing mutations were put under observation for three years. The study found that higher levels of soluble amyloid beta 42 predicted a lower risk of progression to cognitive impairment to a greater extent than lower levels of brain amyloid.
Hanh Brown: Personally, this is an important finding that could change the way we approach Alzheimer's disease treatment in the future. For me, this hits close to home. My mom, my mother-in-law, my brother-in-law, my neighbor, my sister's mother-in-law and I, have watched as the disease slowly robs families of their memories, their ability to communicate, and eventually their mobility.
Hanh Brown: To see that there might be a way to target the disease more effectively is very exciting. It gives me hope that one day we might be able to slow down or even stop the progression of Alzheimer's and give people like me and perhaps your loved ones some of their precious memory back.
Hanh Brown: So today, my guest is Doctor Alberto. Doctor Alberto is a professor of endowed chair at the University of Cincinnati, James and Joan Gardner Center of Parkinson's Disease. He has published over three hundred peer-reviewed research articles and eight books, including Common Movement Disorders, Pitfalls, and Brain Fables: The Hidden History of Neurodegenerative Diseases and the Blueprint to Conquer Them. Doctor Alberto has served as a chair of the Movement Disorder section of the American Academy of Neurology. He recently launched his first milestone study of aging, which you can find at CCBPstudy.com. So, Doctor Alberto, welcome to the show.
Alberto: Thank you, Hanh. I'm so glad to be back on the show. I'm a fan of yours, and I thank you for all you're doing to bring awareness to the latest developments in Alzheimer's research.
Hanh Brown: Thank you for the introduction, Alberto. It's always a pleasure. I'm a student of your work as much as I can understand it, you know, it's deep. I'm honored to have you back. There's so much to learn and so much to share and bring awareness of all your work, so
thank you for the opportunity.
Alberto: I see myself as a clinician primarily, a doctor that sees patients - this is what I love to do. I'm a servant to my patients, and I do research as a vehicle to help my patients. I also think that without research, we wouldn't be able to hope. But I'm careful not to think of myself as a researcher because research is not an end in itself, but rather a means to an end.
Hanh Brown: Thank you so much, I love your work and please keep doing it, and I hope to be a supporter forever, and I look forward to this conversation.
Alberto: So, what is Alzheimer's? Alzheimer's is a neurodegenerative disease characterized by the accumulation of amyloid-beta plaques in the brain. These plaques interfere with the function of neurons and eventually lead to their death, causing the symptoms we associate with the disease, such as memory loss and cognitive decline.
Alberto: Over the past few decades, many clinical trials have attempted to target and remove these amyloid plaques in the hope that this would slow or stop the progression of the disease. However, these trials have largely been unsuccessful, and we've started to question whether we're approaching the disease from the right angle.
Alberto: This led to more direct testing of the amyloid-beta hypothesis and how treatments lower amyloid levels. The most common mechanism for lowering these levels is the development of antibodies, particularly monoclonal antibodies, which bind to a specific part of the amyloid protein, marking it for removal by the body's immune system.
Alberto: This approach has proven effective in treating many types of cancer, but it's still under investigation for Alzheimer's disease. It's our hope that with further research, we can develop more effective treatments for Alzheimer's, bringing us one step closer to a cure.
Alberto: If we really consider Alzheimer's, and neurodegeneration in general, we see a lot of loss. For instance, the brain constituents like neurons and glial cells are declining. We often treat the situation as if something is increasing, but in reality, it's more about something going down. When I said earlier that plaques are accumulating, it's more accurate to say that the formation of plaques is increasing, but the total content of proteins in the brain isn't actually increasing. It's not like the brain is swelling or filling up, rather, it's on a path of shrinking or atrophy.
Alberto: We're losing proteins because they are becoming plaques, and if we only focus on this aspect, it seems like proteins are increasing and becoming toxic. However, this narrative is incomplete.
Hanh Brown: So, if treatment for Alzheimer's disease depends on lowering amyloid beta 42, is it necessary to use different treatments for different people? Some might respond better to medications, while others to lifestyle changes, dietary supplements, or a combination of all these.
Alberto: That's an important question and allows me to present a different side of the story. Our brains are filled with normal proteins that keep our brains growing and nurtured. But what happens in Alzheimer's is the transformation of normal proteins into plaques - something that is no longer functional.
Alberto: We don't usually talk about this side of the story. We only think about the plaques and how to get rid of them. But if we consider that normal proteins today might become plaques tomorrow, and those normal proteins are no longer available to us, perhaps we should consider enhancing the levels of the normal proteins as part of the treatment.
Alberto: We recently tested this idea. We found that people who already have plaques in their brains, but also have high levels of normal proteins, can maintain their normal cognitive functions better than those with lower levels of normal proteins.
Alberto: The future of Alzheimer's treatment lies in two directions. The first involves using a therapeutic approach that applies to most people with Alzheimer's, where we rescue their brains by providing more of the normal proteins. The second direction is personalized treatment. This will depend on identifying the specific causes of Alzheimer's in individual patients, which could vary greatly from one person to another.
Alberto: We're developing programs aimed to understand why a person develops Alzheimer's and how they differ from others with the same diagnosis. This will allow us to treat individuals in a biologically personalized fashion. However, before we reach that point, we can still use the rescue medicine approach to replenish the brain with normal proteins.
Hanh Brown: So, could this understanding of the role of normal proteins be used to re-approach Alzheimer's?
Alberto: That's a great question. The traditional conception of Alzheimer's being driven by the toxicity of amyloid plaques came from observing families with a genetic mutation that overexpresses amyloid. We used to think that the problem was simply having too much amyloid. However, our recent study makes it clear that the problem isn't about how much amyloid there is, but how much normal protein we lose.
Hanh Brown: In San Luis, we have pioneers of the Dominantly Inherited Alzheimer Network (DIAN) and Cohort. This large cohort includes individuals with a genetic mutation, many of whom don't have Alzheimer's, they just have the mutation, and they are worried that they are at risk of developing Alzheimer's.
Hanh Brown: The answer, which was very poignant from them, was "It's interesting that you found this in our cohort because we know that amyloid levels are high. You're saying that high levels are good makes no sense," well, it actually turns out that...
Hanh Brown: It wasn't necessarily clear to them, even though it's been reported that in those who over-express amyloid, like those who have a genetic mutation in either of the three genes (APP, presenilin 1, presenilin 2), they continue to deplete the levels of the normal protein. This happens very early...
Hanh Brown: At least twenty-five years before the onset of symptoms when the levels begin to drop significantly. But a crucial narrative we state is that overexpression of amyloid will result in high levels of amyloid. Still, the functional fraction of the protein levels is low and will become lower as time progresses.
Hanh Brown: Your condition progresses, and at some point, it goes below a certain threshold of compensation. That's when symptoms appear - when the brain can no longer compensate for what's happening in the background, and the brain ends up having less of the crucial protein it needs, hence the symptoms.
Hanh Brown: And that's really a paradigm shift in how we conceive Alzheimer's today. We still tend to think of it as a gain of toxic products, toxic amyloid. But it's really a loss of the normal protein, making it look as if the plaques are the problem.
Alberto: One thing I found to be a very poignant way of illustrating this is that most of us that accumulate amyloid during our lifetimes will not develop dementia.
Alberto: We'll have high levels of amyloid, but these levels will invariably decline to a low level of the normal protein. This correlation is very tight, but the connection between high levels of amyloid plaques and dementia is very loose, very variable, and so that's why reducing...
Alberto: Amyloid plaques haven't been a solution to the problem. But the prospect of restoring normal protein levels could very well be the solution to the problem.
Alberto: So how do we increase amyloid, and are there risks associated with it?
Alberto: Well, we've not looked at it from this perspective. We haven't even thought much about how to increase levels because we have all along been focusing our efforts on how to get rid of it. So the question of how to increase it is becoming a more common question...
Alberto: We are one of several investigators, not just at our university, but we're connected with the Karolinska Institute, Istanbul, and the University of Eastern Finland. We're working on testing the...
Alberto: Value of a modified A-beta 42 protein, a protein that continues to be normal and soluble, with a modification that prevents it from aggregating. So, in other words, it's given to the brain, but in the brain, it might...
Alberto: Lose its function. So we're exploring this one way to address the problem, thinking of increasing the levels of the protein. It would require an infusion system, hopefully not very frequent, because to delay the transformation to plaques would be meaningful...
Alberto: There are considerations of other ways of doing this too, which includes genetic interventions that increase the levels of the protein. There probably will be a number of ways to do this. Progress at this stage remains slow because it's still in the pipeline...
Alberto: It's an antibody that, like many others, cleans up the brain of amyloid, but the report is that there is a modest benefit. And now we're clinging to this thing, thinking we should not abandon amyloid. But this is potentially a mistake, keeping us in the same loop we've been in for so long...
Alberto: If in fact there is a benefit, the benefit may not be mediated by the extent to which it successfully reduces the amyloid plaques, but rather by how much it increases the levels of soluble proteins. And in their discussion of that phase 2 study that demonstrated this unexpected effect of the drug, the authors said: "We don't know why, we don't know what it means," and they left it at that. So fascinating...
Alberto: Should we be taking amyloid supplements or should we be exercising more? What's your take on this? At this point, I would say exercising more is the answer. We don't really know how to replenish the levels of amyloid, but one interesting thing I had no idea about is...
Alberto: I have become aware of the literature on the ketogenic diet. It's fascinating because it has been demonstrated that ketogenic diet and its modifications do have a lot of benefits...
Alberto: Perhaps we could conduct some studies looking at whether that could be one way to increase the levels of amyloid. It may be a better, easier, more natural way to increase amyloid levels.
Hanh Brown: Yeah, I want to cite this example that I learned from you, and it's so important to capture for those who may or may not understand up until this point, but this is what I gather from you. Imagine a forest that has been through a lot - it's been through droughts and wildfires, and now it's full of stumps. But then one day...
Hanh Brown: A team of scientists, let's say Alberto's team, comes in and starts clearing out the stumps. For a while, things seem to be getting better. The forest looks healthier, and the animals are coming back. But then one day a drought hits...
Hanh Brown: And because there are no trees left to store water, the whole forest dries up and dies. This is what happens when you try to clear the aggregated proteins without replenishing the normal protein levels. You might be able to clear away the damage, but you can't restore the health of the system without replacing the protein that was lost. So while clearing the aggregated proteins is very important, it's even more important to focus on protein replacement efforts. Only by replenishing the normal protein levels can we hope to restore the health of the system.
Hanh Brown: The system.
Hanh Brown: So, it's important to understand as consumers, you know, often people like myself caring for loved ones, watch others go through this agonizing process without understanding. We just do what we're supposed to do, what we're told to do, right?
Hanh Brown: But I think it opens all of our minds to be advocates for ourselves and to speak up.
Hanh Brown: It's easy to think that we're victims, right?
Hanh Brown: But I hope that by understanding more, we'll become more empowered, start challenging, asking questions, and just taking more control for our loved ones and ourselves. I really think, you know, if you live long enough, God bless you, at some point in the later part of your life, you may end up with some condition.
Hanh Brown: Which is dementia. Don't take ownership, I absolutely fully agree with all the points. We've talked about protein replacement and the traditional toxic protein theory, right?
Hanh Brown: Is there anything else that you want to make sure that we understand like protein clearance and protein replacement?
Hanh Brown: Right?
Alberto: We are beings constantly changing.
Alberto: The key aspect is that there is a need for balance in all things. That's why we check your cholesterol levels and blood pressure, to make sure everything is at certain levels. These levels are very important for maintaining balance in the brain.
Alberto: The struggle against the fact that we still live in an environment that is becoming increasingly hostile, with toxic pollutants that threaten the brain.
Alberto: The brain reacts very appropriately. One of the ways in which it reacts is by using proteins as a mechanism of defense against injuries like an infection such as the Herpes virus.
Alberto: I was very intrigued by a study that was published about four years ago where a group of healthy people were tested with a beta-amyloid scan to ensure they had no plaques in their brains, in fact, that was demonstrated.
Alberto: They were then asked to sleep-deprive themselves for one night.
Alberto: One night.
Alberto: The very next day, they got another scan to look at whether or not they had amyloid plaques, and surprisingly, they had amyloid plaques now. The PET scan was positive.
Alberto: What was the conclusion of this study? Sleep deprivation is a cause of Alzheimer's. Okay, we looked at those, yeah, sure we see that people tend to have sleep problems and so, it just makes logical sense.
Alberto: But with the exact same data.
Alberto: You could conclude that sleep deprivation is an injury to the brain and the brain reacts against it by forming plaques.
Alberto: This is a method that the brain uses to navigate the challenges brought upon it by the environment in which we live. As we age, the more things we come into contact with, the more likely it is that we come into contact with, the more likely it is that we're gonna be accruing plaques. But what I want to leave you with is a message of hope.
Alberto: Do not fear the plaques. Plaques may well be the reason why many of us live for as long as we do. In fact, we've very much quantified this. There's a protective effect, we see it directly in Centenarians. There appears to be a protective effect. People who have lived well beyond normal lifespans have an equal chance of having or not having plaques. Many of them have zero neurological symptoms even though their brains are filled with plaques.
Alberto: We've factored this in and concluded that we can see a subset of us living way past normal lifespans, not despite the plaques but because of them. If you look at these studies that have been done, we have a linear increase in amyloid plaques such that by the age of eighty-five years, sixty percent of us will have amyloid in our brains. The simple majority of us will be walking around with them, but only ten percent of us will have dementia. This is a five-fold lower prevalence than expected if we assumed amyloid plaques were toxic.
Alberto: This will require changing our approach and adjusting our thinking and our current narrative. If you have an amyloid plaque, you're not on your way to developing Alzheimer's, nor are you a perfect candidate for anti-amyloid therapies. And if you don't have one, you're not free of risk.
Alberto: Our way of thinking about people with plaques is flawed. We don't think of them as normal people with plaques, we think of them as sick people without symptoms.
Hanh Brown: That's crazy.
Alberto: Indeed, it's crazy. No, they are normal people. The plaques are an expression of why they are normal because they are reacting against something appropriately. So, I think that will be the message I want to leave you with.
Alberto: I also want to make sure that this conceptual change allows us to really think of strategies that have a lot more potential for therapy, rather than continuing on the same path just because it has seemed logical in the past. We must let go of ideas that are wrong. All of our fields have had ideas that made sense at some point or another, but at some point, they were shown to be false.
Alberto: It's become clear that there is no correlation between the amount or distribution of the proteins and the severity of the degeneration symptoms, none whatsoever.
Hanh Brown: Yeah, and in the meantime, let's explore some ways to improve your lifestyle, like you mentioned, perhaps the keto diet.
Hanh Brown: Exercise. I mean, I say this without cynicism and so forth. But I think we all should live in such a way that eventually we're gonna get something, right? So not to be sarcastic or cynical about life's outlook, but if we're blessed enough to live long, we should prepare that at some point we're gonna get something. And along the way, you don't need to discover that you have dementia or any kind of illness to start living a healthy lifestyle. Meaning, do it now, do it yesterday. Exercise, eat healthier, try to reduce stress, and sleep better, and so forth. There's a whole lot of things because I hear there's a lot of innovations out there to detect dementia.
Hanh Brown: And of course, your work to further clinical study to get to the source of what causes dementia.
Hanh Brown: But I think in the meantime, since there is no absolute direction, and I don't think there's any app or any sort of technology that's going to predict if I'm going to have it or not, we should just live our lives every day as if we're gonna get something.
Hanh Brown: Absolutely. And we need to be proactive, not reactive, and I fully agree with that. There's so much more promise in preventative measures. They have an impact, even in people who develop dementia. They come from a background of fitness, good diet, good lifestyle choices, they do well. They don't decline rapidly. There are many expressions of dementia, and it seems as if those who do best, those who have a disease but the disease doesn't have them, are those who have already built a lifestyle around exercise, a healthy diet, and social engagement.
Hanh Brown: That's so important. This is another key aspect. If you remove yourself from your peers, if you start to detach yourself from society, your brain loses something in the process. It's like hearing. If you don't use it, it's much worse for the brain. The brain needs a channel of nutrition that comes from the outside in.
Hanh Brown: So when dementia comes, it's going to happen from a point of strength, where we've already enacted the kind of principles that we're saying are important for therapy. If we've used them for prevention, we can be so much better off, even if we have the disease. We've been training to be more equipped to fight it out. It doesn't prevent you, obviously, but I think mental, physical, and spiritual health makes you more equipped to live and flourish really despite the decline.
Hanh Brown: Absolutely. Guys, thank you so much. I always learn so much from you, and I'm sure our listeners do too. Is there anything else that you would like to add in?
Alberto: No, I'm just very thankful that you have introduced these ideas to your audience. I'm delighted to entertain questions. People can reach me via email. I may not be able to answer them all, but I'm always happy to continue the discussion.
Hanh Brown: I'll put your contact in the show notes, but can you let the audience know your email address?
Alberto: Yes, my email address is Alberto.firstname.lastname@example.org.
Hanh Brown: Great. In closing, we often think of science as a dry and heartless pursuit, but sometimes it can provide insights that are both unexpected and deeply moving. Such is the case with a recent study that Alberto conducted with his team on neurodegenerative diseases like Alzheimer's and Parkinson's.
Hanh Brown: Dr. Alberto and his team set out to explore why these diseases are so difficult to treat. What they found was that the root cause of these conditions is not the buildup of harmful proteins in the brain as has been previously thought, but instead it's a depletion of normal healthy proteins that leads to neurological decline.
Hanh Brown: In other words, it's not the presence of toxic substances in the brain that causes these diseases, but the absence of vital nutrients. So this finding offers hope for developing new treatments that focus on replenishing lost protein rather than simply clearing out harmful ones. It also provides a much-needed dose of inspiration for those of us who are fighting these devastating conditions.
Hanh Brown: So next time you find yourself struggling against the odds, remember that even science can occasionally offer us a reminder of what it means to be human. Thank you so much, Dr. Alberto, until next time.
Alberto: Thank you, take care.
Hanh Brown: Thank you for listening to another episode of "The Boomer Living" broadcast. I know you have a lot of options when it comes to podcasts, and I'm grateful that you've chosen this one. Please share this podcast with your friends and family, write a review on iTunes, Spotify, and Google Play. It helps others discover the show.
Hanh Brown: You can also contact us at 7363506842, leave a review, and request content for the show. We love hearing from our listeners. Check out our TikTok, Instagram, and YouTube channel: Aging Media Show, and subscribe for weekly tips on how to best serve the senior population. We want to help them have a great experience as they age. Thanks for tuning in, until next time.