IRA FLATOW: This is Science Friday. I’m Ira Flatow. The brain of a person with Alzheimer’s disease has a few hallmark traits. First, there’s a buildup of plaques of proteins called amyloid beta. Second are tangles of another protein called tau within individual neurons. And the third is inflammation. And while researchers have long thought the inflammation was a byproduct of the disease itself, there’s a growing hypothesis that it may be something else: a driver of the disease progression. That would help explain why researchers have found people whose brains are full of tau tangles and amyloid plaques, but with no outward symptoms of disease. Research on animals has supported this theory, but finding the same evidence in human brains, well, that’s a lot harder. But now a team of scientists thinks they have it. Time-lapsed images of patient brains showing tau tangles and inflammation spreading through the brain in the exact same pattern. Here to explain is the first author of that research, Dr. Tharick Pascoal. He’s an Assistant Professor of Psychiatry and Neurology at the University of Pittsburgh. Welcome, Tharik.

THARICK PASCOAL: Thank you very much for the invite here, and it’s very exciting we are able to do this research. And we’re very excited to be with you here today.

IRA FLATOW: Nice to have you. Well, let’s begin by reminding us what Alzheimer’s does to the brain, at least as far as what most researchers agree right now. What does the process look like, both inside and out?

THARICK PASCOAL: Yeah, what we know about Alzheimer’s, or how I would say what is the most consensual what you know about Alzheimer’s, is that Alzheimer’s disease is characterized mostly for the deposition of two pathological proteins in the brain. And the names of these proteins are amyloid and tau. We know already, it’s very well established that this deposition will start more or less 20 years before the cognitive symptoms of the patient.

THARICK PASCOAL: And we know as well that this protein is somehow associated with the neurodegeneration of the brain, that degeneration of the brain, and this will lead to the cognitive symptoms. This is something that’s established. But what we still don’t know is exactly how these two proteins, amyloid and tau, interact with each other to determine the progression of the disease because we know this is very well established as well. We know that there are many patients, or I would say more or less 30% of the eldery older than 65 years old, have some of these proteins in the brain, but they never developed the neurodegeneration, and they never developed the cognitive decline associated with Alzheimer’s disease. Certainly there is a missing link between the deposition of these proteins and the real development of the disease.

IRA FLATOW: And so what your research is showing is that this missing link turns out to be inflammation. And so how does inflammation fit into this picture of Alzheimer’s now?

THARICK PASCOAL: In fact, we know that neuroinflammation is somehow associated with Alzheimer’s disease for many, many years. There are many evidence from animal models, and even in humans, linking the neuroinflammation of Alzheimer’s disease, but was never very clear how this inflammation plays out between these proteins–this deposition of amyloid and tau protein in the development of the cognition. The most accepted understanding of the disease suggests that the deposition of amyloid and tau protein, are the two main upstream events leading to the progression of the disease.

THARICK PASCOAL: What we’re proposing is that neuroinflammation is, in fact, involved in the development of disease involving the first step of the disease. What we’re proposing is that individuals that have this deposition of amyloid protein in the brain, but also have the presence of inflammation in the brain, are the ones that are going to have the development or the progression of tau pathology.

THARICK PASCOAL: That’s the protein that we know that’s more closely related to the symptoms. In these individuals with the interaction between the amyloidosis in the brain and neuroinflammation in the brain, they will go to develop the pathology. And this tau pathology is what’s going to cause the cognitive symptoms.

IRA FLATOW: So what you’re saying is that we used to think inflammation was a side effect. But now we think it is the actual catalyst for this to progress.

THARICK PASCOAL: It’s actually like this. We used to think neuroinflammation as a by-product of everything that was happening, such as many others, as the atrophy of the brain. But what you are saying here, that neuroinflammation is in fact involved in the beginning of the disease. It is the trigger all of the rest of the process that coming from the neuroinflammation, amyloid and tau pathology.

IRA FLATOW: Let’s talk about what you actually did in the study of people because it’s fascinating. So you looked at the living brains of people in different stages of Alzheimer’s disease. What did you see? What does that progress of inflammation and tau actually look like?

THARICK PASCOAL: We assessed 130 individuals. And we measured brain amyloid, tau, and neuroinflammation. And what we saw was that the individuals that have a baseline–they have the presence of amyloid pathology in the brain and inflammation in the brain–we’re the ones that developed a tau pathology in the follow-up, and were the ones that developed cognitive decline. Developed the symptoms of dementia.

THARICK PASCOAL: We also found that individuals that have in the brain only amyloid pathology, that is believed to be one of the cause of the disease, did not develop the symptoms of the disease. And the ones that have only inflammation also did not develop the symptoms of the disease. Then, our study suggests that the amyloid is an important marker of disease, as everyone know. But amyloid alone, without the presence of neuroinflammation, cannot lead to the progression of the tau, and consequently to the cognitive symptoms.

IRA FLATOW: How do you know that the inflammation is not the result of the disease, and you’re suggesting it’s the cause of the disease? What kind of data, information, makes you so certain about that?

THARICK PASCOAL: This is a very, very good question. As I mentioned in my last answer,I think for a bit more certainty about that, we need more studies with much larger longitudinal follow-ups. But what gives the certainty for us was this, in the longitudinal analysis, we have individuals that have the presence of inflammation and amyloid, and didn’t have tau pathology yet. And in the short follow-up that we did, they developed a pathology. And this temporal association gives us the inference that this would be leading to this tau pathology. I agree that much more studies are needed. And with much larger follow-ups to better ascertain this hypothesis.

IRA FLATOW: Now, is not inflammation an immune system response? I mean, the immune system is usually coming in to protect us from something. Why would the body go in and make Alzheimer’s disease worse instead of protecting it?

THARICK PASCOAL: You are completely right that inflammation has a lot of important and very good functions in our system. But what we believe is that when you are talking about a disease, such as Alzheimer’s disease, the neuroinflammation that’s present, the brain is a chronic neuroinflammation. And in the case of something related to our findings, this was not reported in our manuscript. And this is not studied by us. But it’s postulated, based on many studies in animal models, that what may be happening here is that the microglial cells, that are cells that are there, as you well mentioned, to protect us. The microglial cells try to clean the tau pathology in the brain, they phagocyte the tau pathology in the brain and they try to degrade this tau pathology in the brain. When they degrade the tau pathology of the brain, there are something called tau seeds. And the tau seeds are a part of the tau protein that escape to generate more tau. And along of the way, we release these tau seeds and these tau seeds generate new tau. For this reason, the neuroinflammation that’s there probably in relation to the amyloid pathology that are trying to degrade tau, is in fact propagated tau in the brain.

IRA FLATOW: So the brain has good intentions. But it’s going down the road to hell.

THARICK PASCOAL: Exactly. The microglia has good intentions, but in the end the microglia–and this is very well established in animal model studies, that the microglia may be not so efficient– and in the end of the day, these microglia are going to release these tau seeds and these tau seeds are going to create new pathways of tau in the brain.

IRA FLATOW: That’s really interesting. Would that suggest then, if you give anti-inflammation drugs to let’s say, your lab rats or your animals, and then eventually people, you could test out that theory?

[00:08:53] Dr. Tharick Pascoal: This is a very good point. And it’s very important to mention that we had many trials in the past that try anti-inflammatory drugs to treat Alzheimer’s disease and how these trials fail.

THARICK PASCOAL: But what our study is proposing here, our studies propose here that to have exact moment in the disease where these drugs should be tested. For example, we are proposing that when the tau pathology or the oldest deposition of tau is confined to a part of the brain where it starts, and the patient have amyloid pathology in the same moment, this is the moment that you should try an anti-inflammatory drug. If you try the anti-inflammatory drug much earlier than that, the anti-inflammatory drugs are not going to have any effect because the control group and the disease group both will not have any benefits of the medication because the disease is still not progressing.

THARICK PASCOAL: But if you try too late, when the tau pathology is already progressing for the rest of the cortex, this drug is also not going to work.

IRA FLATOW: How would you know then the exact time when you should give the drug? I mean, you can’t get into the brains of people, can you?

THARICK PASCOAL: This is a great question. We can know this with the image that we use, or the biomarkers that we used in our study, you can take a picture of the brain and you can see where is the deposition of amyloid, of tau, and neuroinflammation there. We propose that if you use these biomarkers to enrich the population of clinical trial to identify the population, that is in the exact moment where the tau pathology progress, we can identify this population to treat in the correct moment.

IRA FLATOW: And how would you be able to do that? Are you in that process now of getting further along and, and trying to give the anti-inflammation drugs at the right moment?

THARICK PASCOAL: I think this is the next step. But I think we need to replicate these findings. And we want follow these individuals for a longer time to better ascertain what is this exact moment. I think we need more studies for in the future being able to perform this clinical trial with the correct moment to treatment.

IRA FLATOW: Yeah, one last question. I remember that the FDA approved the first drug, aducanumab, for removing amyloid from the brain. If you recall, it was a bit controversial because the evidence that it helps actual symptoms, well, that’s still scarce. Is there still a use for this kind of drug if we’re seeing a new role for inflammation then?

THARICK PASCOAL: In the end of the day, the discussions in the field right now, due to the results of aducanumab, may not be optimal to reverse the cognitive decline of the of the patient. The tendency in the field now is to try to find a combination of drugs that can better work in the disease progression.

THARICK PASCOAL: And I think what our results suggest, and I think we’re even suggesting in our manuscript is that, in fact, the combination between drugs such as aducanumab, that aim to mitigate the accumulation of amyloid pathology with anti-inflammators will be the best therapeutic approach for this stage of the disease. Because if you are saying that there is interaction between neuroinflammation and amyloid pathology leading to tau progressions, if you are acting on the two sides in this… in these two pathologies, amyloid and neuroinflammation, we’re going to have a much potentiate effect to benefits patients.

IRA FLATOW: You know, speaking of patients, I imagine, it must have been very difficult for you to find the right patients and for the patients to participate in such a complicated study.

THARICK PASCOAL: Yes, and this is, we are very grateful. And we are sure that the who made the biggest effort for this to happen was not the researchers, were not the staff, but were the patients. Is imposed three different PET scans that take hours lying down in a bed, more MRI, more three hours of cognitive tests, we know how this is incredible burden for the patients. And now the patients were always happy and always able to provide more and more information to us. And we are incredibly grateful of their collaboration and, and is unbelievable how this can be beneficial to the field. And we are very happy to give some some feedback, some results back to them. They think that the big effort pays off.

IRA FLATOW: Fascinating work, Dr. Pascoal. I want to thank you for taking time to explain it to us. It really does look like you’ve made a little bit of an inroad here.

THARICK PASCOAL: Thank you very much. And thank you very much for bringing this to the public. That I think is very important to increase their awareness about Alzheimer’s disease and about the different approach and the different efforts that are being made to treat this devastating disease. Because the public is our final and main end in the end of the day.

IRA FLATOW: We get it and I’m sure they’re very interested. Dr. Tharick Pascoal, Assistant Professor of Psychiatry and Neurology at the University of Pittsburgh. And if you want to read a transcript of this conversation, we’ve got you covered. Go to sciencefriday.com/brains.

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