Mixed Dementia, Explained

Transcript

Intro: I’m Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: On today’s episode of Dementia Matters, we’re going to be talking about mixed dementia or multiple etiology dementia, a condition where brain changes are linked to multiple diseases, which can include Alzheimer’s disease, cerebral vascular disease, Lewy body disease, frontotemporal disease and others. While it isn’t known how many people have mixed dementia due to many only being diagnosed with one type, recent studies have shown that the condition may be more common than previously thought. Joining the podcast to discuss mixed dementias and the NIH’s work studying the condition is Dr. Roderick Corriveau, program director of National Institute of Neurological Disorders and Stroke and NIH Lead for the Alzheimer’s Disease-Related Dementias Summits. Welcome to Dementia Matters.

Dr. Roderick Corriveau: Thank you for inviting me. 

Chin: Dr. Corriveau, how did you get involved in dementia-related research and now with the National Institute of Neurological Disorders and Stroke?

Corriveau: This is a topic that is so close to my heart and though there's nothing more human than the brain. The brain is what makes us who we are. The brain doesn't just control physiological functions such as heart rate and breathing, but really it determines our personality, our mood, our thoughts, our memories. It's really what makes us us, so I'm fascinated by the human condition. I love trying to understand what that means for individuals, families, groups, society, and for myself and to the extent possible I'd like to help people experience a better quality of life. That's what led me to neuroscience. I first started working at the NINDS, or with the NINDS, as a contractor. I was the principal investigator of our program responsible for sharing large numbers of de-identified human DNA samples with clinical data for very large genetic studies. I felt that that type of work had the potential for a significant impact. My interest in the science of dementia grew over the years, in particular as my own father became affected about fifteen years ago. When the opportunity to become a program director at the NINDS for dementia research became available, I was glad and privileged to accept the position.

Chin: I gave a brief definition of mixed dementia in my introduction, but I'd like to know how you conceptualize it and why it is so important to study in the field?

Corriveau: As you nicely summarized, mixed dementia refers to a diagnosis of dementia that is thought to be connected to a mixture – or you might say a combination – of changes in the brain. Multiple disease pathologies appear to be the rule, not the exception, in dementia brains. This is in contrast to the traditional view that within the brain of an individual affected by dementia there would be one clearly dominant or responsible pathway – one disease, if you will, that could be revealed by clinical diagnosis. Since the emergence of the National Plan to Address Alzheimer's Disease about ten years ago, there's been a large shift in the way we think about dementia overall including Alzheimer's disease. That is that for most people, knowing the clinical diagnosis does not reveal the complete or even necessarily an accurate picture of the brain pathologies or dementia disease pathways that are going on inside that person. For example, a person clinically diagnosed with dementia might have evidence of pathological changes in the brain that are traditionally associated with both Alzheimer's pathology – in other words, plaques and tangles – as well as vascular disease. Similarly a person clinically diagnosed with vascular dementia might also have plaques and tangles as well as their cerebrovascular disease. We know from now really a large number of studies that the majority of all dementia cases of people who are 65 and older are mixed dementias, most of the time with Alzheimer's pathology present. Also with cerebrovascular disease present. At times Lewy Bodies may be there. TDP43 proteinopathy may also be present as well.

Chin: You know it's an interesting thing to hear you start by saying how important the brain is. I completely agree with everything you said. It is our identity. It is what makes us human, but then also to hear that we have this very incomplete picture of how the brain really is functioning or how it's affected by all of these different types of diseases. Why has it taken us so long to get to where we are? Why hasn't it been well studied before?

Corriveau: So like so many things in life, there isn't one clear answer. Part of it though is that Alzheimer's pathology – in other words beta amyloid plaques and tangles – was discovered first and it occurs in the brains of most people with dementia. Thus it was a natural place for researchers to concentrate on. Really the focus has largely remained there including with the results of large clinical trials that have been announced in the past, over the past few years and even in recent months. A second aspect is our tendency as humans to want to keep things simple and to fit emerging data into categories that we're familiar with and that we feel comfortable with, such as the plaques and tangles that have been studied for a long time now. A challenge with that is that keeping things simple, it serves a purpose. It allows us to categorize. What we have learned over time though is that that doesn't necessarily align with the biology. On top of that, it may not necessarily align with the biology that is causal – the root cause that leads to dementia. So in our time it has been very popular to say or write that Alzheimer's disease is the greatest cause of dementia and there is a sense in which that is true. Alzheimer's dementia is defined clinically by symptoms, so, you know, it's very true that  the clinical diagnosis of Alzheimer's disease is the one that's most commonly used just because the clinical symptoms match up with clinical Alzheimer's disease. In that sense, you know, clinical Alzheimer's disease is very common and the most common, but extending that to make a rigorous conclusion that we know the cause of molecular mechanisms that cause dementia is not the same thing. I think the field has come to realize that over the past ten years and that has put us in this place of multiple potential pathways to dementia. For example, a key hypothesis, or even assumption, is that Alzheimer's pathology, in particular beta amyloid, causes dementia. Even though it's popular to say that – that Alzheimer's disease is the greatest cause of dementia – the fact is that it's a hypothesis or even assumption that beta amyloid, from a rigorous standpoint, causes dementia. That's a hypothesis that's being tested with increasing rigor over time and including the results that we've been hearing about, clinical trials that have concluded recently or will conclude in the next coming months.

Chin: Knowing some of these barriers and some of the thought patterns that have led to oversimplifying the process – but now we're, of course, more aware in this discussion of mixed dementias happening more often. What is the field doing to better understand this multiple etiology dementia or mixed dementia?

Corriveau: There are several ways to try to get about a better understanding. One is simply the field accepting that we have hypotheses about potential pathways to dementia and investigating them rigorously from a molecular mechanistic standpoint – including in model systems, animal models, iPSC – and learning about causal pathways, causal molecular mechanisms, from a model standpoint. A second is a translational path. Once we have molecular mechanistic understanding, what are the targets that emerge as the most promising going forward? You know, understanding that the current targets that have been popular may or may not result in the outcomes that we want, but being open to new targets and testing them and putting them through their translational steps. Finally when the targets are ready, clinical trials. We know we need clinical trials to test and see whether an intervention on a particular target that's been identified will work and will help prevent or treat dementia. Now, how do we do that? This is where we get to biomarkers. In order to target disease pathways in an individual or potential disease pathways, one has to know which potential disease pathways are active in that person. Is it Lewy bodies? Is it beta amyloid? Is it a vascular process? Is it TDP43 pathology? Is it something else that we haven't identified yet? To know whether those pathways are active in an individual we need biomarkers to recognize that in individuals and that it is a current focus of the field.

Chin: The National Institute of Neurological Disorders and Stroke hosts an Alzheimer's Disease Related Dementia summit to discuss national research goals in dementia research. In March of this year 2022, this summit convened and there was an emphasis on multiple etiology dementia. Can you summarize some of the highlights and key recommendations from the summit?

Corriveau: Yes, one of the major themes is actually the need for precise biomarkers that could identify the myriad of underlying Alzheimer's disease and Alzheimer's disease related dementias processes. I want to just mention now one of the programs that is ongoing, sponsored by the NIA and the NINDS, is called MarkVCID. MarkVCID is a consortium of nine sites and a coordinating center, and the goal of this consortium is to take biomarkers for vascular contributions to cognitive impairment and dementia from a research space into a space where they're ready for large-scale clinical trials. This is a program that just went through a renewal period and is going into its sixth year. We started with 47 different biomarkers proposed. And just to give a sense of sort of the valley of death, the translational pathway, out of those 47 biomarkers that were proposed for vascular processes it's now been narrowed down to five and those five are being put through their paces for clinical validation and scale up for large clinical trials. It remains a high priority in all areas of Alzheimer's disease and Alzheimer's disease related dementias. The summit also recognized that there are opportunities to increase the effectiveness and sophistication of Alzheimer's disease and Alzheimer's disease related dementia's clinical trials, including increasing the use of pragmatic clinical trials. There are a number of ways to kind of increase the sophistication of clinical trials, like adaptive approaches, agile approaches, basket trials, randomized platform trials. Something that sometimes gets a little bit overlooked is that there are things that we can do right now that will improve cognitive impairment including dementia outcomes in the future. There is a lot of implementation science that needs to be done to let us do that effectively with perhaps one of the most obvious examples being blood pressure control. Achieving health equity is a major unmet need across the board in health including in dementia. We must address the needs of diverse populations that have Alzheimer's disease and Alzheimer's disease related dementias. We know that many racial and ethnic minority groups face a high prevalence of dementia and we know that they may be even less likely than other populations to get a proper AD, ADRD diagnosis and have greater difficulty getting access to high quality services and supports. Additionally, racial and ethnic minorities are underrepresented in research studies that inform diagnosis and treatment and that is something that needs to be rectified. Finally, more research is needed to understand the possible link between COVID-19 and long-term cognitive decline including the potential acceleration of Alzheimer's disease pathology, other pathologies that are connected to dementia, as well as symptoms.

Chin: In one of your answers was talking about biomarkers and other non-Alzheimer's disease processes and you brought up MarkVCID as a good example. Are there studies going on looking for biomarkers of the other conditions? The Parkinson's disease, the TDP43, the Lewy body disease.

Corriveau: Absolutely both the NIA and the NINDS support quite a few programs that are making strong efforts to discovering biomarkers in those other disease areas. An example that I'll give is AMP AD, an NINDS program that is investigating molecular mechanisms for Parkinson's disease but also for Lewy body-related dementias including for biomarkers. It's critical that we have multiple irons in the fire, multiple programs that are addressing mechanisms, biomarkers, and clinical research and clinical trials into the multiple potential pathways for dementia.

Chin: Is there a relationship between or among the brain diseases? I mean, do you think that they just simply happen or that one might cause another or that they're just completely independent of each other? Is there any thought as to what's happening in the brain when one finds, let's say, three of these brain diseases?

Corriveau: It's a really good question, so I'll start with something very concrete. There is absolutely a relationship between Alzheimer's pathology and vascular pathology in a really concrete way. That is that cerebral amyloid angiopathy is characterized by beta amyloid being present in the smooth muscle of the vascular walls, and on top of that cerebral amyloid angiopathy is a very common feature of a clinical Alzheimer's disease diagnosis. Already there is that kind of really – it almost feels logistic as I describe it but really, it's a scientific relationship. Now, in terms of relationships among the different types of pathologies. Do they interact with each other? Do they augment each other? You know, there are some data available on that. For example, ApoE. We know that ApoE can have an impact on vascular health. We know it can have an impact on tau, and we also know that traditionally it's considered the greatest genetic risk for Alzheimer's disease. It's kind of a hub of things, but ApoE isn't the only one that can bring out those kinds of relationships. It is too early to tell the extent to which these processes run in parallel and kind of are additive versus synergize with each other and it's a really important question. It gets also to the question of root cause. I think as we try to understand these questions about the relationships among the potential disease pathways and we get to rigorous answers, it will help us tremendously in terms of understanding root cause and that will be just an amazing and wonderful thing.

Chin: You probably aren't able to answer this one either, Rod, but I'm wondering, are there certain combinations of brain diseases that lead to more decline in people? We know that everyone's decline in dementia is unique to their own experience, but we also hear of cases of people declining quite rapidly. I'm wondering if, as we look at autopsy studies, is it true that having multiple diseases means you're going to decline faster than people with just one disease?

Corriveau: Yeah, so a few different parts to an answer. You're quite right. Of course, I'm not able to answer it fully but I can give you food for thought for sure. So the first thing that came to my mind when you're asking that question is autosomal dominant Alzheimer's disease. I think that sometimes we forget that autosomal dominant Alzheimer's disease is a very early onset, rapid decline, and there is a lot that can be learned from that and I think a lot that we haven't yet learned from that. I think that is one thing that's very important. We also know that in autosomal dominant Alzheimer's disease, we can dispense with the traditional thoughts that it's all Alzheimer's pathology. There's certainly a vascular pathology that also occurs. So it is not only an opportunity to better understand rapid decline but it's an opportunity to continue investigation in, perhaps a very specific type of example, the interactions among pathologies. If I go to sporadic Alzheimer's disease, certainly we know from the religious order studies and memory aging studies that as you add pathologies, there is a faster and faster decline that correlates with the addition of pathologies. I think there is no doubt that it's better to have zero pathologies and then the next best is to have one and the next best is to have two. This is where I kind of run out of gas because in terms of the detailed answers of why that is, that is a topic of research right now, important research.

Chin: Because mixed dementia is more common than any single condition, is it fair for us to say that when we look back to all of the clinical case reports – and for the clinicians that are listening, their clinical experience – is it fair to say that that variability that we see in the “standard Alzheimer's patient” that that variability is more likely related to multiple pathologies and or other chronic conditions impacting the brain than it is just a variation?

Corriveau: I mean I think that is the best hypothesis right now, but honestly just from my own personal perspective, I don't know. Why do I say I don't know? Because I don't. Also because a single pathology can be correlated with wildly different diagnoses and different people. What you’re saying may be correct, that if you have somebody who has Alzheimer's pathology and they have vascular pathology that person may look different in terms of their clinical diagnosis than if they have Alzheimer's pathology alone, if you can find somebody like that. What's also true is somebody with tauopathy can have FTD or AD or a different disease and we're starting to understand, you know, some of the details of the tau. There may be a slightly different tauopathy in Alzheimer's disease versus a different disease, but I think it's – these are really difficult questions that I don't think there's going to be necessarily one answer to.

Chin: I'd like to transition from identifying, diagnosing, to sort of treatment. You know, if a person does have multiple etiologies causing their cognitive symptoms and impairments, it would seem more difficult to develop effective treatments to cover them all. Instead of just addressing one thing, now we're addressing two or three or four. How is the therapy landscape altered by this condition of multiple etiology dementia? How is the research impacted that deals with clinical trials and therapy?

Corriveau: Well, I'm going to start with good news first. The good news is that as collectively there is an openness to multiple potential pathways to dementia, that there will be interventions that are targeted against multiple pathways to dementia. It's going to broaden the overall approach that the field will take and that will give us more shots on goal, more opportunities to be right about our hypotheses because, after all, we're talking about hypotheses here. Now another thing that is directly connected to that is it's going to be really important to know whether the candidate-disease mechanism targeted by an intervention is active in the people who are being treated in a clinical trial. I want to pause for a second and just think–  we can all think of clinical trials, at one point or another, where it wasn't necessarily the case that it had even been asked whether the particular pathway that was being intervened on was active in the person. We've moved, I think, to a state now where we acknowledge that it's important to ask and to find out. Thus pathway-specific markers have become increasingly critical in understanding dementias and this is the importance and the question of biomarkers. We really need biomarkers that identify critical disease pathways in people who are alive so that we can target those pathways for intervention.

Chin: So, Ron, I'm going to ask you to try to imagine this question from the perspective not as a researcher, but as the clinician or a patient or a member of the community, because given that we don't have any disease modifying therapies yet for any of the neurodegenerative diseases that we're talking about, is there a clinical benefit in knowing if someone's dementia is due to Alzheimer's disease versus Alzheimer's disease plus cerebrovascular disease or Lewy body disease?

Corriveau: Yes. I'm going to keep the answer simple and then I'm going to give a couple of examples. Just from a strictly clinical standpoint, it's super important for people to know, for their families to know, if they have a Lewy body component to their dementia. The treatment in the clinic is immensely impacted by whether or not Lewy bodies are present, and the person's trajectory is immensely impacted. There are medicines that when given to people who have Lewy body dementia make things much, much worse. It's terrible for the families. It's terrible for the patients. So yes, it makes a difference. In terms of knowing whether there are vascular issues, treating blood pressure or having a person's blood pressure under control to try to prevent them from having a stroke or an additional stroke – critical. Life-changing. The answer is yes. Now there are other questions too and they get to be more personal. For many people they would like to know what their trajectory is going to be as much as possible. It can give people a better sense of themselves and where things stand to have a clear diagnosis. That is very helpful for planning and also just for understanding, so that is also a yes. The earlier the diagnosis, the better. I think it helps with the individual for reasons that I've already mentioned and it also gives them the greatest opportunity to take advantage of new, emerging treatments that we don't have yet but we may have soon.

Chin: And in thinking about interventions, can you share with our listeners the recently updated campaign by the National Institute of Neurological Disorders and Stroke? The one I'm thinking of is called, “Mind Your Risks”.

Corriveau: Absolutely, I'm happy to. In 2016, we launched a public health campaign, “Mind Your Risks,” to raise awareness of the connection between high blood pressure in midlife and risk for stroke and dementia later in life. Your listeners can go to the Mind Your Risks website at http://mindyourrisks.nih.gov for more information about the connection between high blood pressure, stroke, and dementia. Keeping your blood pressure in a normal range can help reduce your risk for stroke and dementia. You can take steps to get your blood pressure in a healthy range. We advise people to learn your blood pressure number and monitor your blood pressure often, make healthy lifestyle choices like eating healthy foods and exercising regularly, talk to your healthcare provider about your risks for stroke and dementia, and make a plan to manage your blood pressure and other risk factors. To that end, we've also developed a guide to help people talk to their healthcare providers about managing their blood pressure.

Chin: It's a great website, Rod, and I really appreciate all the flyers and the colorful images that the organization has put together. We've printed them out for our own clinic to share with our patients in primary care and in the memory clinic. It's a great effort and it really goes to speak to the importance of these things that don't necessarily require a medication. They can at times, but there's lots of things people can do to improve their blood pressure without taking a pill and you guys cover all of it in your flyers. To conclude today, what most excites you about the next five years of dementia related research and where do you hope the field moves?

Corriveau: What excites me is to continue to improve our understanding of the multiple potential pathways to dementia in individuals and the need for biomarkers to, in individuals, understand, target, and intervene, respectively, in critical disease pathways that can lead to a personalized medicine approach that focuses on disease processes in all individuals affected by dementia. I'm excited about spurring the development of new therapies and prevention strategies for AD, ADRD through discovery of therapeutic targets that are the root cause of dementias – biomarker identification or validation, clinical trial readiness studies, early-phase clinical trials, and trials of promising interventions to prevent dementia or improve care. Finally, address modifiable risk factors that we already know about and that we can act on right now, such as high blood pressure, cigarette smoking, and obesity. Discover and address new risk factors and biological mechanisms that contribute to the development of cognitive impairment and dementia, both for pragmatic approaches based on existing knowledge such as blood pressure control as well as new therapies. What excites me is the growing understanding, appreciation, and action toward interventions that are developed with and including diverse populations that have historically been underrepresented in clinical studies.

Chin: Well with that, thank you, Dr. Roderick Corriveau, for joining us on Dementia Matters. We certainly hope to have you back on in the future.

Corriveau: Thank you so much. I really enjoyed it.

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