Alberto Espay, MD, MSc, Professor of Neurology, UC College of Medicine and Director and Endowed Chair of the James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders, talks about how restoring a brain protein could make a difference in patients with Alzheimer’s.
I wanted to start with just a couple of very quick questions, Dr. Espay, about Alzheimer’s disease. How serious a problem is it?
ESPAY: Very serious. As we age, it’s one of the most common conditions that we’ll face.
Any estimate how many people struggle with it now and exponentially five, 10, 15 years from now, what we could be looking at?
ESPAY: As we age, the prevalence will continue to increase. For now, we’re very much hovering around six million people across the United States. So, it’s really quite a devastating condition, one that we will have to ensure to think carefully on how we’re going to approach it if we’re to truly have successes.
Currently there’s no cure for Alzheimer’s?
ESPAY: No cure, and the problem is that we have been very much intent on having one approach that seemed very sensical against Alzheimer’s, but it has become clear it must be reconsidered, and that is targeting amyloid.
Let’s talk about that a little bit. You said it was kind of like a one size fits all or this one approach. People hear the word amyloid or amyloid plaque, because we have heard a lot about that, they might not have some context. Can you describe what that is and what its role was going to be, or it is thought to be in Alzheimer’s?
ESPAY: Amyloid plaques are the end result of amyloid beta, a normal protein that comes in mostly two different variants, amyloid beta 42, that means 42 amino acids of a peptide of a large protein, amyloid beta 40, that is with 40 amino acids. When facing any type of infectious, biological or toxic injury, amyloid beta 42 (the most aggregation-prone) becomes aggregated. That aggregation is what can be recognized on autopsy studies and more recently on PET imaging as amyloid plaques. And they’re plaques because they are no longer in a soluble state, they are firm. They are like little, tiny clumps or stones that we accumulate as we age.
So, you were talking about the fact that there are these clumps or these aggregates. Can you tell me a little bit more?
ESPAY: Every evidence that we’ve accumulated, including data that has now come from many clinical trials, point at the fact that the plaques are a consequence, not a cause and reducing their load doesn’t do much of anything for people.
So, tell me a little bit about your team’s study, how you went about doing it and ultimately what you found.
ESPAY: The background here is that we have had many trials in which drugs have reduced amyloid but patients have not improved. And then, here’s the main paradox. All of us are accumulating amyloid as we grow old, but not all of us develop dementia. By the age of 85, 60% of us have amyloids in our brains and only 10% of us develop dementia. So, there is a fivefold lower prevalence of dementia than would have been predicted if amyloids were toxic. So, what we decided to do was to try to seek the solution to this paradox by looking at the difference between people who already had amyloid but were normal cognitively versus people who had amyloid and had dementia. And what we asked from the data is whether the difference could be explained by higher levels of soluble proteins, the normal protein and the precursor of amyloid, explaining the preservation of normal function despite having amyloid plaques. And that’s exactly what we found. We used the data from 600 amyloid-positive people participating in ADNI, the Alzheimer’s Disease Neuroimaging Initiative. We found that the difference between people who were normal versus people who were demented was that those who were normal had higher levels of the soluble, normal fraction of the amyloid beta 42 peptide. It didn’t matter how high the amyloid plaques in the brain got, anyone who had higher levels of amyloid beta 42, were normal. In fact, we determined that most of those above a threshold of 800 picograms per milliliter had normal cognition. This is the first time that we can fully explain why so many of us can have amyloid in our brains and yet be cognitively normal.
When you find that it may be this peptide or this protein that we need more of, in theory, what does that lead to, increasing this finding a way to increase this protein as a preventative measure? Can you explain that.
ESPAY: Absolutely. That is exactly what we would want to accomplish, which is the opposite of what we’ve been trying to do for decades. Rather than cleaning up the insoluble amyloid, which may be doing nothing, we may want to increase the levels of the soluble, normal protein. Adequate levels of soluble, normal amyloid beta are very important for normal function. And it goes without saying that proteins must be in their normal state to be able to function, that the minute they change their configuration and become something like plaques, they no longer can function. So, in fact, we think that the replacement strategies of the proteins we’re losing may be the most important strategy in the future to fend off the development of dementia in people who may be accruing amyloid plaques as a result of something, the nature of which remains invisible.
Now this finding that you and your team kind of flies in the face of conventional wisdom. Let me ask you, first of all, how has this been received in the scientific community? Because you have 20 years of “it’s these plaques,” and now you’re looking at something that may not.
ESPAY: There have been mixed reviews. There are those that say, well, we finally have an explanation that answers a number of the puzzles that we couldn’t explain. But there is still a very large group intent on keeping the same approach we’ve had for a while on the idea that we’re very, very close to getting there. In fact, we aren’t. Our investments into anti-amyloid approaches have been in the billions of dollars and we really have nothing to show for it. In neurology, we’re a bit of an unusual species. We have been unable to falsify hypotheses after negative trials. In medicine, trials are created with the idea that to prove or reject a hypothesis, you do a clinical trial. If the trial is positive, you confirm your hypothesis. If it’s negative, you’d reject the hypothesis. We almost never reject hypotheses in neurology. We think our hypotheses are perfect and it is the imperfect trials that actually are to be blamed. If only we had perfect trials, then our ideas would have been confirmed.
So, what’s the next step? When you have this new body of knowledge, what do you do?
ESPAY: We have begun the preclinical work, that is, working on animal models, to define the safety and potential toxicity of strategies aimed at increasing the concentration of the peptide to reach normal levels. That is going to require quite a bit of work. For that we have now a collaboration with colleagues at the Karolinska Institute in Stockholm and together, in fact, we’ve created a company called Regain Therapeutics to help facilitate all the work that will be necessary to getting us to a point where we can translate that knowledge into the first proof of concept clinical trial in people with Alzheimer’s.
You had mentioned that, you know, billions of dollars have gone into drug discovery and those have been mixed. Aducanumab was just approved, but there was a lot of concern about that drug?
ESPAY: Yes, this drug was approved because we’re unable to falsify hypotheses. We have remained stuck on the idea that lowering amyloid is the only way to go despite many drugs that have lowered amyloid to the same extent than aducanumab. And when the FDA reviewed the data on aducanumab, it noted that it reduced amyloid very well but there was no translation into benefits. The FDA approved this drug with the “expectation of future benefit,” even though the trial did not show any of it. In fact, this is one of 14 other drugs that have done the exact same thing, that is reducing amyloid but not translating into any kind of clinical benefits. It’s very problematic at many levels. To me, the most important problem is that, at the end of this intellectual discussion we’re having, there are patients that have nothing to benefit from this therapy and much to suffer. And so, I think it would be important for those in the community, especially patients themselves, to recognize that, although they hope that this is “better than nothing”, aducanumab is worse than nothing. If by nothing we mean placebo. In nearly half of the trials in which the experimental drugs have lowered amyloid, those in the placebo arm have done better than those in the treated arm. That means that we’ve been unwillingly harming people out of the idea that amyloid lowering must be the only way to go.
Why is it so important to look at these new avenues? To look at new theories? To keep researching for something that will do better?
ESPAY: It’s critical because we have to get successes in people. We cannot simply be just stubbornly tied into a theory because it’s a beautiful, compelling idea. If an idea isn’t panning out with the data, we need to move away from that idea. And I think, in this situation, there are many careers at stake, with many people worrying about their legacy. But, in fact, this should not be about academic legacies. It should be about people. And I think that’s why we need to change. Change in this situation is a necessity. It’s not in any way intended to be just disruption for the sake of it, but rather because we have to get it right for our people. We have already plenty of evidence to know that the status quo, the way we’ve been doing things, is incorrect and we need to change.
Last question for you. Is there anything I didn’t ask you that you want to make sure that people know?
ESPAY: Alzheimer’s isn’t one disease, its many diseases, so there will be a variety of different other biological treatments that are going to be given to individuals that just have the diagnosis by virtue of how we make that diagnosis at the bedside, but no demonstration of whether the biology the treatment addresses is at play in them. It’ll be very important for people to know that when considering participating in any future studies of interventions to slow disease progression, they must require from their physicians an answer to the question, “why is that study for me?” If every one of us is different and if every one of us has a different brand of Alzheimer’s, then a test or a bioassay should be used to determine who the best candidates for that therapy are. If that’s lacking, then the trials will continue to show futility. I think the concept of cure in neurodegenerative diseases, especially Alzheimer’s and Parkinson’s, need to be reformulated much in the way oncology did for cancers. Once they moved away from the idea of “curing cancer,” there was so much progress made in so many different types of cancers according to the individual biology driving the individual expression of those different types of cancer. So, I think that’s roughly where we need to go. The brain obeys the same laws of biology and physics than the rest of the body organs. So, we really need to start applying similar concepts and aiming at a future of precision medicine, that is, a future where we really act as if we mean that not two individuals are the same.
Just a quick clarification, the protein you mentioned amyloid beta?
ESPAY: Amyloid beta is, A beta 42, the most common…
Forty-two, OK.
ESPAY: Amyloid beta 42 and amyloid beta 40. Forty-two is the most important because it’s the sticky version of the protein.
The name of the company… Regain?
ESPAY: Regain Therapeutics.
And that is outside of University of Cincinnati?
ESPAY: Yeah, it was created in Stockholm.
Stockholm, OK. And what is the purpose of Regain?
ESPAY: To develop the types of peptide analogs that cannot aggregate and can be infused into the brain preserving their function without turning immediately into plaques.
How long until you could get preclinical studies out?
ESPAY: The first two studies in animal models, running parallel, should be completed within the next six months, but we will require a variety of other studies. We need to measure how much of the experimental peptide gets into the brain, what’s are the effects, including any potential toxicity.
Right.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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