Host Fiona sits down with the researchers who are learning that cognitive decline has many faces: it's a constellation of biological breakdowns, many of which may be detectable - and even treatable - long before symptoms appear.
What if we could slow - or even stop - the brain’s decline? Cognitive disorders like dementia affect millions of people worldwide. As Canada faces an increasingly aging population, and more people become caregivers for their elderly loved ones, healthy aging of both brain and body are top of mind for many. Luckily, researchers are revealing a far more hopeful picture as they explore how actions in early life can impact brain aging. They’re learning that cognitive decline has many faces: it's a constellation of biological breakdowns, many of which may be detectable - and even treatable - long before symptoms appear.
Featured guests:
Ina Anreiter, Assistant Professor in the Department of Biological Sciences at the University of Toronto Scarborough.
Peter Zhukovsky, Assistant Professor in the Department of Psychiatry at the University of Toronto and Scientist at CAMH.
Julie Ottoy, Assistant Professor in the Department of Medicine Neurology at the University of Toronto and Scientist at Sunnybrook Research Institute.
This work is supported by the Tavares Foundation, GJ Garden of Life, and CIHR’s Institute of Aging.
Dr. Julie Ottoy 00:00
[theme music] I guess maybe my path was a bit unconventional in the sense that I started with a Bachelor of Science in chemical engineering and then a Master’s of Science in biomedical engineering. I think I just had, like, one introductory course at the end of uni on neuroengineering, but I do remember sitting in that class and thinking like, “Oh, this is it. This is what I want to do.” It was kind of a love at first sight kind of thing, I guess.
Fiona 00:35
This is Bold Minds: Future Leaders in Canadian Brain Research. I’m your host Fiona Sanderson. I work at Brain Canada, where our mission is to bring together funders and researchers to enable health innovations for Canadians. The Future Leaders program is made possible thanks to an anchor gift from the Azrieli Foundation and matched by Brain Canada through the Canada Brain Research Fund. Come along with me as we journey into the bold minds and labs of researchers who are redefining our understanding of the brain. [music ends]
[rousing music] As Canada faces an increasingly aging population and more people become caregivers for their elderly loved ones, healthy aging of both brain and body are top of mind for many. Cognitive disorders like dementia affect millions of people worldwide, but today’s researchers are revealing a far more hopeful picture as they explore how actions in early life can impact brain aging. They’re learning that cognitive decline has many phases. It’s a constellation of biological breakdowns, many of which may be detectable and even treatable long before symptoms appear. This episode, we’re exploring the full picture of brain protection and aging prevention. Because cognitive health isn’t just about what you eat or how much exercise, but also about how well you sleep, the health of your brain’s blood vessels, and more. This is Bold Minds. [music ends]
Today, I’m joined by...
Dr. Ina Anreiter 02:10
I’m Ina Anreiter, and I’m an Assistant Professor in the Department of Biological Sciences at the University of Toronto Scarborough.
Fiona 02:17
Dr. Anreiter and her team are interested in whether disrupted sleep can accelerate cognitive decline in conditions like Alzheimer’s. They’re investigating how tiny chemical modifications inside our DNA affect biological processes like sleep, and unlocking new strategies to treat aging-related cognitive decline and neurodegeneration.
[whooshing] I’m also joined by…
Dr. Peter Zhukovsky 02:41
I’m Peter Zhukovsky. I’m an assistant professor at the Department of Psychiatry at the University of Toronto, and I’m a scientist at the Center for Addiction and Mental Health.
Fiona 02:51
Dr. Zhukovsky and his team aim to understand what the early biological changes are that lead to dementia. They’re searching for factors we can detect using blood tests that can serve as markers of worsening brain and cognitive health. They hope to improve quality of life for both aging individuals and their support systems.
[whooshing] And I’m also joined by…
Dr. Julie Ottoy 03:13
Julie Ottoy. I’m a scientist at Sunnybrook Research Institute and an assistant professor in the department of medicine, neurology, at University of Toronto.
Fiona 03:23
Dr. Ottoy and her team study mixed dementia. The most common form of dementia, it occurs when Alzheimer’s disease combines with vascular disease. They aim to clarify how and when blood vessel and immune system changes in the brain contribute to mixed dementia so they can better predict who might benefit from personalized treatments targeting blood vessel health. Ina, Peter, Julie, welcome to Bold Minds.
Dr. Peter Zhukovsky 03:47
Thank you.
Dr. Ina Anreiter 03:48
Thank you. Glad to be here.
Dr. Julie Ottoy 03:49
Thank you.
[theme music]
Fiona 03:54
Ina, I think most people are familiar with the idea that our genes influence who we are, our behaviors. But you also study how our behaviors affect our genes. And I think that’s fascinating, this process called biological embedding. Can you tell us about that? What is biological embedding? How do you study that?
Dr. Ina Anreiter 04:12
So, we can think of our genes as a blueprint that we are born with, right? It is our DNA. Every single cell in our body has the same DNA. It doesn’t change across cells. But that DNA is just a blueprint. It needs to be made into a molecule that’s called RNA, which then ultimately gets made into proteins, which are the building blocks that do everything in our cells. And so, what we experience throughout our lifetimes changes that process of how our DNA gets made into RNA and gets made protein, which ultimately can change how the cell functions.
Fiona 04:53
So, you used the fruit fly as a model for your work. And I think people may have heard that fruit flies are something researchers work with, but I’m not sure it’s generally known why. So, tell us, what makes fruit flies a genetic powerhouse model? What can they tell us about our brains?
Dr. Ina Anreiter 05:09
The history of why fruit flies became a model for genetics actually goes all the way back to the start of the 20th century. There’s a very famous researcher in our field called Thomas Hunt Morgan who in the early 1900s had a laboratory. They were studying a variety of different organisms. And they one day noticed that they had this one single fly, had white eyes instead of red eyes, which is the usual color of eyes of fruit flies if you have noticed them at home in your kitchen. I mean, they’re everywhere. [chuckles] So, that was a key moment in genetics research because Morgan and his team then decided to figure out what made that fly have white eyes and whether that characteristic—that unique characteristic could be inherited. And so, now if we fast forward, a lot of the essential discoveries about how genetics works have been first described in fruit flies. And so, there’s a few characteristics that make them really good models. One is they have a short lifespan, so you can look at the inheritance of traits really quickly. Two is they have a lot of offspring, so you have a lot of data to work with. And now when we’re thinking about modern genetics and why we use them now, what makes fruit flies a good tool for genetics is then we can go in and manipulate the changes that we observe and see if we reverse those changes, for instance, we’ve reverse the behavior or the phenotype, so we can prove causality.
Fiona 06:43
One of the questions you work on is understanding the long-term effects of sleep. So, most people, of course, know sleep is important. It recharges us, gives us energy. But your research suggests it might be doing something very specific inside our cells at a molecular level and can actually affect us beyond just the next day or two, all the way into our elderly years. Can you walk us through what you’re finding about the connection between sleep disruption and cognitive decline?
Dr. Ina Anreiter 07:09
So, we know that in a lot of cognitive decline disorders like Alzheimer’s disease and other neurogenic diseases, one of the symptoms is worse sleep or more fragmented sleep. People don’t sleep as much and people don’t sleep as well. On the flip side, we also know that one of consequences in the brain of fragmented sleep are things like altered protein homeostasis. So, you get this aggregation of proteins that shouldn’t be there, and they cannot be cleared out. They’re usually cleared out during sleep, sort of like a housekeeping of the cells at night. So, we don’t really know yet which direction this goes in cognitive disorders. Is it, you know, that sleep is fragmented and that worsens those sort of protein housekeeping problems that you see in these disorders or is it that you have protein aggregation and that worsens sleep? So, my research is trying to investigate a little piece of this puzzle. Basically, looking at one specific molecular mechanism that we know results both in fragmented sleep phenotype and these cognitive decline phenotypes as well as protein aggregation, and we’re trying to figure out how it does that.
Fiona 08:23
And you’re focused on something called m6A. So, it’s a tiny chemical modification that affects how our DNA instructions get carried out. Can you explain what m6A is in plain terms and why you might think it might be a key player in brain aging?
Dr. Ina Anreiter 08:38
So, what we found is that when we delete this chemical tag m6A in neurons in the brain, what we see in our flies is that they show fragmented sleep, which is one of the comorbidities with a lot of neurogenic disorders, but they also show altered protein aggregation in the brain and learning and memory deficits. And so, you take those three things together and they’re very indicative of neurodegenerative disease, but we really have no idea at this point how and what this chemical tag is doing and how it’s doing it to result in these neuro-geno phenotypes. So, that’s why we’re interested in studying it.
Fiona 09:23
Peter, you study the neurobiology of psychiatric and mood disorders, and they’re linked to neurological conditions like Alzheimer’s. I guess I think of these as a bit of a chicken and egg situation similar to the sleep and cognitive decline that we were just talking about with Ina, coexisting conditions. But your work suggests that they are temporally linked, and depression may actually be a risk factor for developing Alzheimer’s. Is that right? Can you tell us more about that?
Dr. Peter Zhukovsky 09:47
Yes. Absolutely. So, depression has been identified by a number of studies, actually, by an agglomeration of evidence, really, as one of the many risk factors for Alzheimer’s disease and dementia more generally. Of course, understanding the neurobiological pathways that link psychiatric conditions like depression alongside sleep, but also a number of other [inaudible 10:11] modifiable lifestyle factors in mid and early, late-life, is really important to building robust prediction models of who is at the highest risk for developing cognitive decline and potentially Alzheimer’s disease.
Fiona 10:26
So, your focus is on early detection and risk prediction of treatment-resistant depression, which is then predictive of dementia. So, why is this important? Like, is there some kind of course correction that can be done to prevent negative outcomes, and how early are we talking here to be able to make a difference?
Dr. Peter Zhukovsky 10:43
Absolutely. So, some studies suggest that treating depression, especially treating treatment-resistant depression in older adults who are perhaps in their sixties, in their seventies, might actually help modify, to some extent, the risk of those older people getting dementia or Alzheimer’s disease, right? In fact, some of the numbers that link depression with Alzheimer’s disease kind of suggest perhaps around 7% of the modifiable risks for dementia is actually attributable to depression. So, in some people, if we can treat depressive symptoms, if we can successfully figure out what treatments work best for those late-life depression patients, then we might actually change the trajectory that they’re on and perhaps prevent them from developing cognitive decline. But I think the picture is really quite complex because we really try to understand the neurobiology of the mechanisms that link depression to Alzheimer’s disease, right? And so, that’s partly why we study a large number of proteins, you know, these kind of very wide-ranging assays of proteomic markers and look at how those can predict the onset of even more minor, less easily detectable cognitive changes, brain health changes. As we get more and more data, as we get larger and larger data samples, we try to integrate these various data modalities. We try to improve our models—predictive models that we have, and one way of doing so is, of course, to use both imaging data, genetic data, and understand how the genetic risk factors perhaps interplay with the environment and how they interact with the environmental risk factors that are more modifiable, and how those can be linked to these measures of brain health that can actually glean from the neuroimaging data.
Fiona 12:32
So, beyond diagnosis or risk prediction, could these markers tell us something about why someone’s cognition is declining and help point toward the right treatment?
Dr. Peter Zhukovsky 12:41
I think we have to be cautiously optimistic about the causal inferences that we can make. In some of the studies that we’re looking at, of course, there is the temporal differences between we have these proteomic assessments perhaps ten years before we look at brain and cognitive health, and so we can kind of infer, you know, some directionality and what’s driving the results. But building these predictive models, I really view it as an essential step to testing them in these rigorous clinical trial studies, right? We can then, you know, try to understand, what are the biological markers that are predictive of worsening cognition or worsening depressive symptoms or non-remission of depressive symptoms? Right? So, I think that’s a really critical kind of effort that, you know, we’re involved in and a lot of our collaborators are involved in that is really kind of pushing precision medicine, precision psychiatry, precision neurology, if you will, and are actually leading to these clinical trial designs that allow us to test whether those predictive models are actually working prospectively in the real world.
Fiona 13:45
Wow! That’s great. Julie, most people have heard of dementia and Alzheimer’s, but I’m not sure it’s widely known that there are different types of dementia and that a combination of types is possible. So, you studied the latter, mixed dementia, which is less well known. Can you explain what mixed dementia is and why it’s actually the most common form of dementia?
Dr. Julie Ottoy 14:05
Yeah. So, mixed dementia is a term that kind of literally means the combination of multiple causes of dementia. The one that I study is specifically where we look at Alzheimer’s disease in combination with cerebrovascular disease. If we just think about people in their eighties, hypertension is present in almost 100% of people in their eighties, right? So, the lifetime risk for vascular disease is very high. It’s been over a century now that Alzheimer’s disease was first described, but only very recently, like, just last year here in Canada, we now have treatments that don’t just target the symptoms like memory problems, but they actually target the disease itself. What I mean with that is that these drugs can remove a sticky protein, which we call amyloid, from the brain. And that’s super exciting because if we can change the underlying biology early enough, then one day we might be able to prevent the symptoms from ever showing up. Now, while these treatments are very exciting, we do have some problems here. And one of these problems is that in some patients, that same protein, amyloid, does not only build up around our neurons, around the brain cells, but they also build up around the blood vessel to a larger extent, and we call that cerebral amyloid angiopathy. And CAA makes our vessels more fragile, more brittle, and that can lead to side effects when patients get this treatment. So, in my research, we look at biomarkers. It can be based on blood samples or pictures of our brains, so brain images, that gives us an indication about, you know, if CAA is going on and to which extent it’s going on in the brain. Now, the difficulty with current CAA biomarkers is that they are end-stage. So, we kind of miss CAA in patients who are in the earlier stages, and that’s a problem especially now because the treatments are also moving towards earlier stages, right? So, we’re especially interested in biomarkers of inflammation that are linked to early-stage CAA, because we think that inflammation might be one of the earlier signs that these blood vessels are getting into trouble.
Fiona 16:27
So, you all work on this sort of large umbrella concept of cognitive decline, and you’re all working at risk in some way. So, Ina, this idea of sleep disruptions having negative long-term effects on our cognition, so is the answer as simple as, and I’m reluctant to ask, getting more sleep? Like, does age factor in? Like, sleep becomes more important once you hit, I don’t know, 40. What about time of day or quality of sleep?
Dr. Ina Anreiter 16:55
So, we know that all of those things are important and that things do change with age, but it’s not just a question of choosing to get more sleep, and I think what we need to understand is in the context of neurodegenerative diseases whether the sleep is a cause or a symptom. So, we might be getting less sleep in a neurodegenerative context, and we know that sleep is important to maintain our brain health, so it might make neurodegenerative symptoms, actually, even worse, or it might be that because our brain is unhealthy, we are getting less sleep and our sleep is affected. So, I think figuring out which way this relationship goes will be really important to understand whether maybe there is interventions that are aimed specifically at improving sleep that might improve neurodegenerative outcomes and brain health, or maybe there is interventions that are aimed at some of the others like removing those protein aggregates and then that will improve sleep without us having to target sleep per se.
Fiona 18:06
And so, Peter, you’re looking at depression as a risk factor and, Julie, vascular health. And, you know, we consider some of these things modifiable risk factors. Peter, you mentioned that before. It’s something we can actually change to improve the prognosis as opposed to, for example, a genetic predisposition to a disease. But the idea for something like a blood test for dementia, it almost sounds too simple. So, what makes a blood-based marker reliable and feasible to actually be used clinically?
Dr. Peter Zhukovsky 18:34
First of all, I think it’s from just learning more about some of Julie’s and Ina’s research, I feel like there is a fair amount of overlap in some ways. You know, we’ve been looking at more perhaps even shifting it a bit earlier in the preclinical kind of stages, rather than, you know, a lot of the samples or a lot of the populations we’re working with, they don’t have really pronounced cognitive symptoms yet. So, I think that’s an important thing to note. But we do already have some blood tests for Alzheimer’s that have been approved by the FDA, and in a way, like, what I’m working on is building on top of that, right? Like, it’s kind of going beyond the blood [and I’m 19:11] looking at a wide range of proteins that are circulating in blood plasma and looking at how those can be, in addition, predictive of the risk for dementia, right? Because as Julie also kind of mentioned, there are potentially different pathways to developing these cognitive problems in late-life. In terms of what we do is, we really operationalize or we conceptualize brain health as things we can see on a MRI scan, you know, loss of gray matter volume in some ways as a marker of very early kind of signs, you know, the [inaudible 19:44] for potential risk for dementia down the line.
Dr. Julie Ottoy 19:50
If I just think about a clinical perspective, like, when do patients come into the clinic? Right? Typically, they don’t come in the clinic in the very early stages, and nor will they come in with just one pathology. Typically, when our patients come to the clinic it’s with symptoms, and there’s already a lot going on in the brain. So, they have mixed pathologies. So, what we need are these biomarkers, which can be based on blood, to capture each of these separate pathologies. And ideally, down the line, that will also be early on before the symptoms develop. And in my opinion, if we look at, what is a good biomarker? Then first of all, it should be one that is specific. Biomarkers that are specific for each of these core pathologies that are happening. So, these biomarkers ideally should reflect the underlying biological mechanism. And that is a challenge, especially a challenge with the blood biomarkers, I would say, because they are peripheral. And if I look at inflammation, which is a part of my research, it’s even more complex because inflammatory biomarkers in the blood can be altered with, for example, arthritis, acute injuries, infections, autoimmune disorders. So, some of these biomarkers may be increased in these cases while also be increased with Alzheimer’s disease. So, a lot of these biomarkers that we currently have for inflammation are nonspecific, and that is something that the field is working on right now. Another important one is that we do want to try to detect earlier. And if I look then from a vascular perspective, I think this was mentioned by Peter before, there’s a temporal lag between when the vessels start to change versus when our biomarkers change versus when we show cognitive symptoms. So, with vascular biomarkers, currently they are mostly picking up the end-stages. Like, the injury is already there and it’s often irreversible. So, we may want to try to focus on biomarkers, whether that’s imaging or from the fluid, that [speaks up 22:01] more the function of the vessel and the vessel physiology and morphology. I think that will be important as well. Another important parts for blood biomarkers, like important factors, are that they should be accessible and that they should be reproducible across different populations. If we look at, for example, different ethnoracial groups, for example, or replicable across [inaudible 22:27] or replicable across different sites where they are collected.
Fiona 22:33
Of course, that’s so important. You know, especially in a broad Canadian population, you want those to be accessible for different communities. So, if we are able to find, you know, these reliable early biomarkers, does that tell us that these conditions are in some way inevitable, or how modifiable are modifiable risk factors?
Dr. Julie Ottoy 22:54
There’s one study that comes to mind right away which is—I don’t know if you guys heard about, is the SPRINT-MIND study. I think that is currently the best evidence for risk factor-targeted intervention for patients with vascular cognitive impairment and dementia. Because what they did in that trial, they looked at people who have hypertension and increase cardiovascular risk profiles, and then they applied a more intensive blood pressure control in those patients as opposed to standard care. And what they found was that this group of patients that got some more intensive blood control, that those had less vascular injury over time. But what was most interesting is that there were also cognitive benefits, but that they did not show up right away. So, it took several years before you really started to see that kind of separation between the group that had the intensive blood pressure control versus the standard care. So, I think it’s a bit of a long game, that will be my answer, and I think that fits with the title of the episode as well. I think this trial is just very encouraging. It targets the hypertension, so the risk factor, and it kind of shows that if we intervene early and consistently that we may be able to change the trajectory at least to some extent. But it’s not a complete solution on its own, in my opinion. It’s just—it’s like one actionable piece of the puzzle, essentially.
Dr. Peter Zhukovsky 24:26
Finding potentially sensitive and specific biomarkers, it really opens the door to essentially offer more cure as well. Right? Like, there’s, of course, the question of what intervention is going to be the most impactful? Which intervention would suit this particular patient versus, you know, this particular person, right? We actually know from other fields, or historically we have some evidence that has worked really well in stroke prevention, for example, right? Like we have the Framingham score. We have, the statin intervention, right? That is targeted specifically for cardiovascular health, and it has produced benefits for reducing the risk of stroke and ischemic events that can really have quite consequences on someone’s quality of life. [inaudible 25:09] you said it’s not perhaps the complete story of we’ll be able to prevent 100% of cases, but we may be able to target therapies to people who really need them the most, right?
Dr. Julie Ottoy 25:22
It’s so important. And, obviously, cognitive decline is complex, so the solution is probably going to also be multifaceted. So, it’s really important research being done.
Fiona 25:32
Over the course of this podcast season, as you know, we’ve been hearing about the work of early career researchers, fellow awardees of Brain Canada’s Future Leaders in Canadian Brain Research grants, and they’re studying a wide variety of brain functions and conditions. But it strikes me for how broad the subject matter is, there’s so many commonalities. So much to be learn from other areas of research. So, in your own experience, how important is collaboration? Has it changed anything about your work?
Dr. Ina Anreiter 26:01
Collaboration is, I would say, one of the most important things in my work. We are only one person. We can only do so much work, so we tend to focus on a small piece of the puzzle. But unless we have an idea of what everyone else is doing, we don’t understand the whole picture, and the collaboration comes in. It is really, really important to frame your own research and the question that you’re working on within the bigger question.
Dr. Julie Ottoy 26:30
Yeah, I agree with Ina. I think if there’s one thing in the academic space that I’ve learned it’s that you cannot do things alone. Dementia is too complex in general, as we’ve been talking about. I mean, it’s important to dream big, but you’re never going to solve this by yourself. So, you really need—I’ve just been very grateful for all the collaborators and the mentors and supervisors that I’ve had along the way. And, of course, also thankful to the grant agencies and our patients, especially too, because they are the ones who make our research possible in the first place.
Dr. Peter Zhukovsky 27:05
I can only echo what both Ina and Julia said. Collaboration has been very critical to being able to do what we have done so far, and, you know, I think it will continue to be a very critical element of anything that—any of the projects that we do. And especially within Canada, of course, you know, I’m based in Toronto, we have others in Ottawa and Montreal, but also across the world. You know, I’m an early career scientist so I really kind of look up to some of the leaders in the field that—you know, both in Canada and internationally and try to learn and take inspiration from some of the work that people do across the world, and try and talk to them as much as possible and, you know, try to advance our research together.
Fiona 27:49
Well, thank you, Ina, Peter, Julie, for chatting with me today, and thank you all for joining us on Bold Minds.
[theme music]
Dr. Ina Anreiter 27:55
Thank you. It was a pleasure.
Dr. Julie Ottoy 27:57
Thank you so much.
Dr. Peter Zhukovsky 27:58
Thank you.
Fiona 28:03
Bold Minds is a Brain Canada production with support from the Azrieli Foundation. Our executive producers are Jillian Donnelly and Kate Shingler. Our lead producer is Jess Schmidt, with editing by Morgane Chambrin. Thanks for listening.
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