TGen Talks: Joanna Palade, Ph.D.
Karie Dozer [00:00:04] I'm Karie Dozer and this is TGen Talks. Alzheimer's disease, a brain disorder that slowly destroys memory and thinking skills in otherwise healthy adults, is the seventh leading cause of death in the United States and is the most common cause of dementia in older adults. As many as 6 million older Americans have the disease. Although it's not known exactly what combination of factors causes Alzheimer's. One thing is certain the earlier the disease is diagnosed and treated, the better. A team of scientists from Tien and City of Hope have just released the findings of a study that could lead to a simple lab test to indicate the onset of Alzheimer's disease in a patient years, before their symptoms would be obvious to their doctor and even their friends and family. And our guest for this episode of TGen Talks is Joanna Polade. What is it that you do here at TGen?
Dr. Joanna Palade [00:00:59] Thank you for the invitation. So I am Joanna. I'm a staff scientist in the neuro Genomics division. So we are really interested in studying all manner of neurodegenerative conditions. We're talking Alzheimer's, Parkinson's, ALS, MS. If it has something to do with neurodegeneration, we probably are interested in it and we're actively researching it. So we are more specifically interested in finding biomarkers in human bio fluids that can help us predict, diagnose and monitor diseases that are degenerative in nature.
Karie Dozer [00:01:32] For our science 101, what is a human bio fluid?
Dr. Joanna Palade [00:01:36] Anything that can come out of a person that is liquid is a human bio fluid. So we're talking plasma. Could be tears, could be saliva, could be urine, could be spinal fluid that bathes your brain. Really, anything that we can easily access, that has information that we can use for to understand someone's health.
Karie Dozer [00:01:55] The specific bio fluid you're looking at in this study, in these findings is plasma. And you're looking at Alzheimer's disease, which is obviously a diagnosis that probably strikes fear in a lot of Americans when they hear it. What is it you were looking for in this study?
Dr. Joanna Palade [00:02:09] So we know that Alzheimer's disease strikes early and for about a decade or so, maybe even more, before you actually know you have it. Your brain is undergoing these changes, and the pathologies happening in your brain is undergoing neurodegeneration. So our hope is to look for markers that can help us predict the disease, and so that we can tell someone in the clinic early, hey, in ten years you might get sick, or in five years or you'll never get sick. You're fine. You don't have to worry about it. So the idea is to grab something from the plasma that can tell us about a person's health so that we can help clinicians with these patients. Because once you are diagnosed late, your window of time for action is very brief. And if you could tell someone ten years before, you know, there'll be time for intervention, there be time for lifestyle changes, for drug disease, for therapy. So there's just more of an opportunity for the person to do something about it.
Karie Dozer [00:03:03] Is there's still a problem with diagnosing Alzheimer's disease specifically. Doesn't it look like a lot of other disorders?
Dr. Joanna Palade [00:03:10] Yes. So that's one big problem that we had in this study. So we went off of the diagnosis that was given to the patient in the clinic. But in reality you can only really make a diagnosis for a patient, a real true official diagnosis after that, after you've had a chance to look at the brain and look at what's in there, Alzheimer's looks like a lot of other diseases, and it looks like other types of dementias. And it's not uncommon that a clinician might give someone an Alzheimer's diagnosis, but really they have something like vascular dementia or dementia with Lewy bodies or something else entirely. And it's important because the therapies might be different for these different types of diseases. So you don't want to be pursuing therapy for Alzheimer's when you really have something else entirely, and it's not helping you at all.
Karie Dozer [00:03:53] So what is it you were seeking to discover you're looking to identify Alzheimer's, or the likelihood of Alzheimer's years before an official diagnosis?
Dr. Joanna Palade [00:04:02] Exactly. So we know that our bodies, all of the cells in our bodies, are making these tiny little vesicles that they put out into circulation, into your saliva, into your urine, into everything. And because they come from all tissue types, some of them probably come from the brain and from brain cells where they carry information that comes from the brain. So the idea is that if your brain is healthy, those vesicles will have information that tells us your brain is healthy. If it has a disease, those vesicles will tell us that it has a disease. And so our hope here was to get blood from patients, get the plasma, and then find the vessels and see what's inside to better understand where the patient is in terms of their brain.
Karie Dozer [00:04:43] How many patients did you look at and what did you do.
Dr. Joanna Palade [00:04:45] So we looked that over 100. I think we had something like 134 people. So they were divided into a group with Alzheimer's, a group with MCI or mild cognitive impairment, which is, sort of like a stage before you got Alzheimer's, where you really just have, like, small deficits in memory, subtle, subtle changes, that maybe only your loved one can even notice. And we also had a group of control patients, so healthy patients that did not have, any kind of diagnosed neurodegenerative condition. So we were looking to see if there are changes that we can detect between those people.
Karie Dozer [00:05:21] And what did you find?
Dr. Joanna Palade [00:05:22] So we found hundreds of different transcripts that were changed between healthy people and the Alzheimer's people. But more importantly, our collaborators at UCSD, the pathologists are very thorough with our cohort, with our group of people that we were studying and followed them closely and had many visits with them and curated information carefully. And so what have we found is that even though they had initial diagnosis of Alzheimer's or of MCI or of controls, over time that changed. And also when some of them went to autopsy because they passed away, we found that sometimes the diagnosis didn't quite match. So we were able to make groups that were a little more distinct and that were not just based on what you see in the clinic when you go. And so I think that's really, one of the wonderful parts of this study. And it's information that many people don't really have. And we were able to make these groups a little more clearly, a little more defined, where we could follow the disease trajectory better.
Karie Dozer [00:06:22] In this study, you're looking for markers that might let you inform a patient that indeed, they're headed for a probable diagnosis of Alzheimer's.
Dr. Joanna Palade [00:06:31] Absolutely. So we found that some of those markers that people have early on seemed to correlate with how much longer until they develop the disease. So, for example, you might have a low level of a specific marker when you're ten years away, and then it goes up when you're five years away. And then when you're right, when you have the disease, it's gone up even more. So. There are some markers that we can use to not only predict who's going to get the disease, but also what the timeline might look like. So we think that's immensely valuable.
Karie Dozer [00:07:00] Did this group teach you anything about, that group of patients who isn't diagnosed with Alzheimer's but is diagnosed with mild cognitive impairment, or at least presents to your study with those symptoms? How do they look different? Or do they.
Dr. Joanna Palade [00:07:14] They do look quite different. More different than we would have thought because the initial thinking was, well, MCI is just, you know, a step to Alzheimer's, but that doesn't seem to quite be the case. It very much seems its own thing. It's very own defined category. And parts of those groups look quite different from other parts of the group. So I think what we're seeing is that some of those people might eventually go on to Alzheimer's and some might not, and I think that would be very valuable to note. Unfortunately, the size of our group isn't terribly huge, so we don't have enough people that will go to one or the other to really make those claims quite yet. But that's absolutely something to do in the future with a bigger cohort where we see what is a trajectory for most people with MCI and where are they going, and can we find markers that predict that pathway?
Karie Dozer [00:08:03] Is it possible one day in the future to truly diagnose Alzheimer's with one of these biomarkers?
Dr. Joanna Palade [00:08:10] That is really our hope that you could just go to your clinic. Maybe they'll prick your finger, draw a little bit of blood, and then run a quick, cheap, easy test in the clinic that can tell you, hey, you're headed towards it or you're fine. Don't worry about it. We're not quite there yet, but that's what we are working towards.
Karie Dozer [00:08:27] And what about the idea of diagnosing even earlier than perhaps the time frame? In your study, you're looking at about a ten-year span of time.
Dr. Joanna Palade [00:08:35] We are. Yes. It's possible. I think the further away you get from the disease, the smallest those changes are. So there might be a cutoff where it's quite a little bit too early to tell or it just becomes a little more uncertain. But even ten years before the disease, is there a lot of time to start exercising or start eating healthy? Or maybe enroll in a drug trial?
Karie Dozer [00:08:54] Having results like this probably makes you want to start a next chapter of research. What's the next chapter as far as you're concerned? What would you like to study next? Knowing what you know from the findings of the study.
Dr. Joanna Palade [00:09:07] So we had a cohort that was 100 plus people. But the reality is that a study like this needs to be done with a thousand plus people. There's immense variability from person to person, and you want to capture all of that. And like we've been talking about, MCI can look like many different things. Alzheimer's. You can be in many different stages. So I think we need a much, much bigger studies to confirm all of these findings. And if we did, I think the next step would be to partner with some kind of a company or a group that does more of bioengineering to see how we can make this an easier diagnostic type of test. Because right now we get the samples and we do the sequencing ourselves, but that's not really feasible. The idea is that this would be cheap and easy for a clinician to do.
Karie Dozer [00:09:51] What else? What do we know about mild cognitive impairment? You mentioned that sometimes it's a stop on the road to Alzheimer's and sometimes it isn't. What else? What do we know and what else is there to find out?
Dr. Joanna Palade [00:10:04] So we know that early on your brain starts to undergo neurodegeneration. You will not have any symptoms. You will not have any issues. You will never know that's happening. And then usually what happens a couple of years later, you will start to notice very small lapses in memory, or lapses in your cognition or your ability to have meaningful social interactions. And oftentimes it's loved ones that even notice that. And then those people we might see in the clinic at that point there is pathology in the brain. But what's really interesting and what's sort of uncertain is where that's headed for some people. A year later, you might have full blown Alzheimer's and you might be very sick for other people. You'll just stay there for the rest of your life. And it's something that you can manage fairly well. And for other people it might develop into a different type of dementia. And. And so it'd be really valuable to understand what the pathway looks like for a person to be able to take those appropriate steps.
Karie Dozer [00:10:59] For someone listening who is wondering what is the genomics component to this? If you're just measuring the amount of marker in a bio fluid, what part of your method actually involves genomic medicine?
Dr. Joanna Palade [00:11:13] So all of the patients vesicles that we grab from the plasma to look for biomarkers were sequenced. So the RNA was fully sequenced for everybody. It's when you're looking for markers, you don't want to just pick 1 or 2. You want to look at everything there is to know. So we're talking thousands and tens of thousands of markers that we looked at for every single person to identify those couple, you know, 50, 20, ten that are going to be useful. We also had genetic background information for all of our cohorts. So we know, for example, that there are certain genes, certain variants of genes that make you more at risk or less at risk for Alzheimer's. So we were able to use that information as well.
Karie Dozer [00:11:56] Obviously, a lot of people fear that they have a genetic predisposition to Alzheimer's or another similar disease. What part does that play in the people you seek out to take part in this study? How important is it to study people who don't have a genetic predisposition to a neurological disorder and those who do.
Dr. Joanna Palade [00:12:16] That's a really great question. And then really good point. For a long time in the history of Alzheimer's disease research, we focus on the people with the rare mutation and the rare this and the rare that, because they were the more interesting group and more likely to get the disease. But the reality is that the majority of people with Alzheimer's don't necessarily have some very specific rare marker, and they've been understudied and overlooked. So we don't seek out very specific people. We have a mix of everything in our group, but the goal here is to study that majority of the population that has Alzheimer's and does not have some magical array or marker that tells you yes or no.
Karie Dozer [00:12:55] If you were to talk to somebody for five minutes about this study and you were to say, what is the most exciting finding, what do you think is the headline for this that you want everyone listening to know about?
Dr. Joanna Palade [00:13:05] I think our most striking finding that surprised even us is that we can identify these changes that are associated with the disease five years on, ten years on, 15 years before someone actually develops the disease. I think this is tremendously valuable for making a test that somebody could use to predict the disease. And it's something that gets us very excited about the next steps.
Karie Dozer [00:13:30] Bottom line, how accurate do you think your models are going to be and how much how much more is necessary to be studied?
Dr. Joanna Palade [00:13:39] Yes, that's a great question. So we were wondering the same thing, and we made some models based on the data that we saw, to see how well we can predict that somebody is going to get the disease just with the data that we have right now. And we're looking at maybe like an 80% accuracy, like 80% of the people were identified correctly. The ones that were intended to be further out from their disease. So that was, I think, encouraging that we can pick the people that are going to develop it quite soon. And there's also probably a lot more information that we can add to this as well. So just using the plasma biomarkers, we're looking at about 80% accuracy. But we could add, you know, new markers. We could add information about their genetic, status, about the clinician's findings, about their behavior. So I think there's room to improve upon the score for sure.
Karie Dozer [00:14:30] Joanna Pallotta, thanks for explaining your findings. Thanks for your time today.
Dr. Joanna Palade [00:14:34] Thank you for having me.
Karie Dozer [00:14:36] For more on TGen’s research, go to TGEN DOT ORG SLASH NEWS. The Translational Genomics Research Institute, part of city of Hope, is an Arizona based nonprofit medical research institution dedicated to conducting groundbreaking research with life changing results. You can find more of these podcasts at TGEN DOT ORG SLASH TGEN TALKS, Apple and Spotify and most podcast platforms. For TGen Talks, I'm Karie Dozer.