What's known and what's still to learn about Alzheimer's disease

Host Amber Smith: Upstate Medical University in Syracuse New York invites you to be "The Informed Patient," with a podcast that features experts from Central New York's only academic medical center. I'm your host, Amber Smith. Many, many mysteries remain to be solved about the development and progression of Alzheimer's disease. Today I'm talking about where things stand with computational neuroscientist Chris Gaiteri. He's an associate professor of psychiatry and behavioral sciences at Upstate and the newest Empire Innovation Scholar, and his research focuses on Alzheimer's. Welcome to The Informed Patient, Dr. Gaiteri.

Chris Gaiteri, PhD: Thanks, Amber. Happy to be here.

Host Amber Smith: You're a computational biologist. What does that have to do with curing Alzheimer's?

Chris Gaiteri, PhD: To cure Alzheimer's, what we expect is that we're going to have to process some big data related to the brain. And you're probably more used to hearing big data in the context of large tech companies, but actually we have big data on the brain and Alzheimer's disease, and so you need people like me to do math and statistical processing of that data in order to sort of extract key signals that are actually going to be the things that we're going to need to monitor and and treat in Alzheimer's disease.

Host Amber Smith: So your doctorate is in neuroscience. For the work that you're doing on Alzheimer's, do you team up with medical doctors on your various research projects?

Chris Gaiteri, PhD: Some of my closest colleagues are MDs. Some of them see patients. Some of them see patients and do research. Some of them are fully in research. But they're great to work with. And I think in general they're very motivated because a lot of them come from this background of just they can't handle telling patients, "there's really very little we can do for you." So that's driven them to research. So they tend to be really highly motivated individuals, and they're great to work with.

Host Amber Smith: Now, in your work, you're searching for what changes happen inside the brain that lead to Alzheimer's, is that right?

Chris Gaiteri, PhD: Exactly. There are a few big studies that generate a lot of our data. These are studies where older people volunteer. They sign up to be studied. And we'll give them cognitive tests every year. We'll monitor things like their diet and their stress levels. And once they pass away, many of these people have volunteered to donate their brains, and so, you're exactly right. Once we have those brains and we know the history of these people, we can then look at molecular and cellular things happening inside those brains and compare them between people with Alzheimer's and people without Alzheimer's.

Host Amber Smith: For years, we've heard experts blame "plaques" and "tangles" as responsible for Alzheimer's. Can you explain to us what those are and whether they play a role at all?

Chris Gaiteri, PhD: Sure. They were discovered about 100 years ago by Alois Alzheimer, who is the doctor that the diseases is named after. And the plaques are a buildup of protein that occur outside of your neurons, outside of your brain cells. And the tangles you can picture as pretty much what it sounds like, a tangle of yarn, but that tangle is going to be inside of the cell. And both of these contribute to Alzheimer's disease. In fact, to have Alzheimer's disease, you need to have a post-mortem examination of the brain, and you need to find both of these to really have a definitive Alzheimer's diagnosis. A lot of times people will, their doctor will say, "Oh, you have Alzheimer's." That's not actually definitive without this post-mortem examination, where you actually observe plaques and tangles in the brain.

Host Amber Smith: So do the plaques and tangles cause Alzheimer's, or are they a symptom of it?

Chris Gaiteri, PhD: When we measure plaques and tangles, they can explain about 30% of the dementia that we observe. They can explain about 30% of cognitive decline. So they're clearly an important component, but there's also clearly other things that are leading to dementia, which is what we really care about, right? We don't care how many plaques and tangles you have in your brain. We care about can you function in society? Are you having a good life in your older years? So they're a component of the cause. But the evidence suggests they're not the entirety of the cause. The reason that we're so focused on those has to do with some very rare genetic mutations in the genes that lead to plaques and tangles. And, in this very rare case, you get a very severe and early form of Alzheimer's disease. So that's really where the focus on them as a cause has come from. But in the broader population, there's clearly many other things which are contributing to causes of dementia.

Host Amber Smith: Do you have your own hunches about what is causing dementia?

So I have hunches, but they're really driven by data. It's not just that I'm pulling these things out of the air. We do have some additional mechanisms that we -- the royal "we," myself and others -- are investigating, in experimental labs where we'll use CRISPR (genome editing technology that's short for Clustered Regularly Interspaced Short Palindromic Repeats) will use genetic tools to engineer cells to modify these mechanisms and then see if we can sort of recapitulate Alzheimer's in a dish. That's kind of how we're investigating these new causes. So yes, there are some things on the horizon that we're testing that I think are very interesting. So you mentioned genes as a potential cause of some types of Alzheimer's. How often does Alzheimer's run in families?

Chris Gaiteri, PhD: It's very rare for the inevitable form, what we call familial Alzheimer's, to run in families. It's a very rare situation. Typically in that case, you'll have this genetic mutation that essentially guarantees you'll have Alzheimer's disease. And that's a very rare situation. When that happens, you get Alzheimer's disease at a significantly younger age, even as early as 50, or slightly younger. You'll begin seeing symptoms, whereas typically you'll be 65-plus, 75-plus, where you would typically have normal Alzheimer's symptoms, the general form of Alzheimer's disease. So it's really rare to have this genetic component of Alzheimer's disease. However, there are hundreds of genes that give you a little bit of risk. So when we're talking about familial Alzheimer's disease with a strong genetic driver, that's a single genetic mutation that's doing the work there. In general, there is a genetic component to Alzheimer's disease, but it's much more distributed across the genome where hundreds of genes are contributing a little bit, which makes it much harder to predict because you have to aggregate across the entire genome. And even then it's sort of a much fuzzier, more difficult-to-predict situation.

Host Amber Smith: This is Upstate's "The Informed Patient" podcast. I'm your host, Amber Smith, talking with computational neuroscientist Chris Gaiteri, the Empire Innovation Scholar in Upstate's Department of Psychiatry and Behavioral Sciences.

So, how did you get into the field of neuroscience?

Chris Gaiteri, PhD: I remember back in high school thinking that I wanted to study something where I would never be bored, and I had this vague idea that the brain sounds pretty complicated. That would be an interesting thing to study for the rest of my life. And, that turned out to be true. I'm sure there are many other fields which are also equally interesting, but for me, I wanted something where there'd always be something new. There would always be something that we don't understand. And, neuroscience has turned out to fit that bill.

Host Amber Smith: What led you to focus on Alzheimer's?

Chris Gaiteri, PhD: That's somewhat of a more pragmatic issue. I'm interested in treating a variety of mental illnesses and diseases, in particular the ones that affect society the most, that are the most common, that are the most severe. And Alzheimer's is right at the top of the list. And also pragmatically, fortunately, recently there's been a large increase in funding for research in this disease. So it makes it actually feasible to study that disease as opposed to some more rare or neglected diseases where there just isn't the funding to actually study them.

Host Amber Smith: I'm curious about how you analyze or you look for the genes or proteins or molecules that are responsible for Alzheimer's. You mentioned some people when they die, they donate their brains to research. So at some point someone's working on tissue, or blood samples. Are there imaging scans involved? I mean, what else is done to help you look for these genes and proteins and molecules?

Chris Gaiteri, PhD: You're right, there's definitely a tissue involved. There's a large freezer farm. I can remember walking through 80 freezers in a long hallway full of brains of people who have donated their brains to Alzheimer's disease research. So it's really great to have those resources. One thing we have done also, as you suggest, is we give yearly or every other year, brain scans to individuals who are in these studies so that after they pass away we have a really nice three dimensional image of the brain, and we also do fMRIs (functional Magnetic Resonance Imaging) so we can look at the activity of their brain as well. So combining the activity of the brain with gene and protein information is something that I'm really interested in right now because we have the ability to do that because we're scanning people relatively soon before they die, and then we have their tissue after they die. So we can actually combine those together, which I think is going to give us a better, more unified, more effective kind of practical definition of Alzheimer's disease.

Host Amber Smith: Did you first have to learn what brain changes are normal as we age? And, is there a consensus in the scientific community about that?

Chris Gaiteri, PhD: That is relevant because while dementia and Alzheimer's are not part of normal aging, you basically almost never see them in younger individuals, right? So there must be something about the aging process that sort of primes the brain or puts it in this position where it can transition into Alzheimer's and dementia. So yes, there are a couple of projects that actually study gene expression prior to getting Alzheimer's disease. But one of the real challenges is that you can only get one time point from the same brain. So we'd really like to follow people when they're 40, 45, 50. I would love to have brain samples from the same individual multiple times, but that's simply not possible to obtain. You can't just sample from the brain.

So what people will typically do to try to study normal aging and the transition into Alzheimer's is to look at blood, specific cells in the blood, or potentially sometimes you can get cerebral spinal fluid by doing a spinal tap. Of course, that's somewhat unpleasant to do, so it's difficult to obtain that kind of data from the same person over time. So what we have to do is sort of a cross-sectional design where we look at many, many people, sampled at one point of time. But it really does make it difficult to do the sort of study that you're talking about where we study normal aging and the transition into Alzheimer's disease.

Host Amber Smith: Do you have any ideas about whether inflammation plays a role in the development or the progression of Alzheimer's?

Chris Gaiteri, PhD: Yeah, inflammation has really been a recent sort of star of Alzheimer's research. Back in 2010 when they started doing some really large genetic studies of Alzheimer's disease, multiple genes that were related to microglia, sort of a major inflammatory cell type in the brain, showed genetic variations that were associated with Alzheimer's disease. In particular, there's one called TREM2, where they found in this Icelandic population, which is a really sort of genetically isolated group, you could have a mutation in this inflammatory gene that gave you, reduced your likelihood of having Alzheimer's disease by a third -- which is a big effect for a single mutation. So there's a lot of strong genetic evidence, and genetic evidence is very strong, for inflammation involvement in Alzheimer's disease.

Host Amber Smith: There are several drugs on the market that help people with symptoms of Alzheimer's. So I'm curious about how helpful those are. I'm thinking of medications like Aricept that supposedly support communication between nerve cells. Does that really work?

Chris Gaiteri, PhD: We'd really like a drug that would strike at the causal basis of the disease that would shut down the process that's causing the disease or contributing to the disease. And like you say, these are more about limiting some of the symptoms. So you can have diverse symptoms in Alzheimer's disease, on other than memory loss. You can have agitation and psychosis. You can have a variety of sort of psychiatric symptoms, depression that go along with Alzheimer's disease. So these drugs are more focused at sort of suppressing some of those things. Which is great. But at the same time, they're not that much more effective than placebo and it's also fairly common to have some unpleasant side effects from these drugs as well. So I think for those reasons, that's why when someone comes into the clinic with Alzheimer's disease, it's certainly worth a shot in many cases, but that's why we're not particularly excited to be prescribing these drugs.

Host Amber Smith: The FDA narrowly approved a drug called Aduhelm that's designed to remove amyloid from the brain. It was sort of a controversial move, and it's a very expensive drug. What do you know about that and how well it's working?

Chris Gaiteri, PhD: Yeah. You mentioned it was controversial, and what happened was, there's a committee of scientists that advise the FDA on their perception of the evidence for drugs. And usually that committee of scientists and the FDA are very much in sync. Three very famous scientists resigned from that committee after the committee recommended against the drug and the FDA approved it. So that's unusual. And I think it signals some of the concerns about the cost benefit analysis for the drug, not just in terms of the monetary cost, but in terms of some concerns about side effects that the drug has. So, on the one hand, it's great to be having new drugs approved for Alzheimer's disease. That's what we want, right? But on the other hand, it would be better if they had larger effects and weren't so controversial and it wasn't so much of a close call.

Host Amber Smith: Do scientists think that if we had a drug that removed the amyloid or the plaques and tangles we talked about earlier, would that fix the problem, or not?

Chris Gaiteri, PhD: So these drugs do remove them. Part of the issue is, though, perhaps they're removing them too late. And so perhaps we need to be intervening earlier in the disease and therefore preserving some of the synapses, some of the connections between nerve cells. So that's been sort of the rejoinder to some of the weaker clinical results is, maybe this is the right thing; we're just not delivering it soon enough. And so that's why in a lot of clinical trials, they're focused on people with MCI, with mild cognitive impairment, which is often sort of a precursor to full-blown dementia, the idea being that that may be a more fruitful time for these interventions.

Host Amber Smith: Researchers are still trying to figure out and agree on the cause of Alzheimer's disease, obviously. I wonder if you have theories about what determines whether Alzheimers progresses rapidly or slowly in the individual.

Chris Gaiteri, PhD: So there are a number of factors that can make you resilient to Alzheimer's disease, meaning that for the same amount of plaques and tangles that someone might have, you're actually doing better than they are. And so the question is, that's sort of a factor that would slow the progression of the illness. It would give you a slower rate of decline. And so, what are those things? And, yes, we actually have published papers on what these factors are, and we're doing experiments on them because there is a lot of variability in terms of the outcomes of having plaques and tangles, in terms of having classic Alzheimer's disease in your brain. And so, if we can essentially give everyone a really slow decline, as opposed to a really fast decline, that would be wonderful. And there is that kind of natural variability in the human population. So that is one thing we're studying.

Host Amber Smith: Alzheimer's is just one type of dementia. Do you think your work might shed light on other types of dementia as well?

Chris Gaiteri, PhD: I hope so.

It would be great to have communication across the discipline. It can be challenging, though. So for instance, with traumatic brain injury, which can lead to dementia, a lot of times it really depends sort of exactly the physics of how a particular brain has been impacted. So each case, to an extent, is somewhat sort of unique. And so even within that class of injuries, it's difficult to draw some universal conclusions. And so then to draw universal conclusions between classes of diseases can be challenging, but it's certainly something that we should try to leverage if we can to work together and draw some robust conclusions.

Host Amber Smith: Do you see similarities between dementias and other brain disorders? You mentioned traumatic brain injury.

Chris Gaiteri, PhD: Yes, there are some similarities, a lot. They won't be full blown similarities, though. What I mean is, for instance, you could have inflammation being involved in multiple brain diseases, but we know that inflammation is probably just one component of Alzheimer's disease, and there'll be additional components of Alzheimer's disease. So I feel like there's selective ways in which we can learn about disease mechanisms across brain diseases. We can import knowledge from a specific domain and use that even if we can't import the entire sort of conceptualization of the disease. There's always spots where we can learn.

Host Amber Smith: You mentioned how you work with big data, and you're sort of focused on the cause of Alzheimer's or the treatments for it. Might there be big data that could let us look at possible preventives for Alzheimer's?

Chris Gaiteri, PhD: Yes. I think that's very important to do because it's likely going to be easier to prevent a disease than to reverse a disease. And I think the public's particularly interested in, looking for something preventative for Alzheimer's disease. So it makes sense to the public too, right? In particular, they're interested in is there something in my diet that I can eat that's readily available that's going to prevent Alzheimer's disease? And so I think that that's pointing to some of these studies that are coming out recently about the Mediterranean diet. A lot of times people have shown that you have lower rates of dementia in people who have certain diets, but you never know if it's just due to genetics or the environment or actually what the people are eating. So there's some studies now where they actually do interventions, where they specifically ask people to eat more of a certain type of food and they verify that the person is, in fact, eating their broccoli or whatever the intervention is. And so I think those studies are going to be quite interesting in terms of prevention for Alzheimer's disease.

Host Amber Smith: The field of study you've chosen is just fascinating. I wonder, have you discovered anything that was totally shocking to you about Alzheimer's?

Chris Gaiteri, PhD: So a number of years ago, there was -- this wasn't my finding; this is researched by other individuals -- but this finding that plaques and tangles cannot account for a majority of the dementia that we observe in people with Alzheimer's disease. And so I think on the one hand it's discouraging that plaques and tangles are probably not enough. But on the other hand, they've been so difficult to treat that it's really nice to know that there's this unknown cause of dementia out there, and maybe that's going to be easier to treat. And so that's one of our major focuses is trying to nail down what exactly is that signal, right?

We've measured it. We have cognitive tests from people with Alzheimer's disease. We have their brains after they die. So it is possible to actually find molecular causes related to this dementia that's not accounted for by plaques and tangles. And so going after that is really sort of exciting, and it's been a little bit shocking how big of an issue that is, but at the same point, I'm really happy to be going after something that important.

Host Amber Smith: Well, Dr. Gaiteri, I really appreciate you making time to tell us about your work. Thank you.

Chris Gaiteri, PhD: My pleasure.

Host Amber Smith: My guest has been computational neuroscientist, Chris Gaiteri. He's an associate professor and Empire Innovation Scholar in Upstate's department of psychiatry and behavioral sciences. "The Informed Patient" is a podcast covering health, science and medicine, brought to you by Upstate Medical University in Syracuse, New York, and produced by Jim Howe. Find our archive of previous episodes at Upstate.edu/Informed. This is your host, Amber Smith, thanking you for listening.