The Future of Dementia Research and Care

Alzheimer’s center leaders offer an interdisciplinary, collaborative approach to neurodegenerative disease.

In July, Bess Frost, PhD, a researcher who studies the causes of brain aging and neurodegeneration, moved her lab from the University of Texas Health Science Center at San Antonio to take the helm of the Center for Alzheimer's Disease Research at Brown. As the Salame-Feraud Director of the center, she will foster collaboration among scientists and clinicians at the Carney Institute for Brain Science, the Division of Biology and Medicine, Brown’s affiliated hospitals, and beyond to advance prevention, diagnostics, and treatments for Alzheimer’s disease and related dementias. 

Frost, who is also a professor of molecular biology, cell biology, and biochemistry, joins Edward “Ted” Huey, MD, the associate director of the center, who came to Brown from Columbia University last year. His extensive research and clinical work have focused on Alzheimer’s disease, frontotemporal dementia, and other neurodegenerative disorders. Huey is also the director of the Memory and Aging Program at Butler Hospital and the Martin M. Zucker Professor of Psychiatry and Human Behavior at The Warren Alpert Medical School.

Frost and Huey sat down to talk about the surprising similarities between Alzheimer’s and other neurodegenerative diseases, the importance of collaboration between clinicians and basic scientists to understand their complexities, and how the center will help improve care and find therapies for the growing number of people diagnosed with these disorders.

This interview has been edited for length and clarity.

Thank you both for meeting with me. Dr. Huey, in an interview with Medicine@Brown after you arrived last year, you said one of the things that attracted you here from Columbia was the “opportunity to grow” the Alzheimer’s program. Dr. Frost, what brought you here from Texas?

Bess Frost, PhD

BF: Yes, it was very similar for me. I also really, really liked the people here. Scientists at Brown are doing such innovative and impactful work, but are also just very genuine, nice people. I've always worked at major medical centers, so something that really attracted me to Brown was the multidisciplinary aspect to research on campus. When I came for my faculty interview, I met people who worked in botany, biomedical engineering, and other fields that I don't usually get exposed to, which was very exciting. I have had very frequent interactions with scientists in other fields since I arrived at Brown, just as I had hoped. Interacting with these types of people has given my team and I new ideas for projects, made us think about certain experiments in a different way, and allowed us to learn of certain resources or approaches available to us that we hadn't previously considered.

And then, obviously, the opportunity to grow the Alzheimer's center here and bring everyone together—really, that was the major thing bringing me in.

Would you tell us about your research?

BF: We spend a lot of time thinking about why neurons die in Alzheimer's disease and related dementias and what factors drive brain inflammation. A major focus is figuring out how pathological forms of tau protein negatively affect cellular function. Tau tangles are one of the diagnostic neuropathological features of Alzheimer’s disease, along with amyloid plaques, but aggregates of tau protein are also in a bunch of other neurodegenerative disorders—collectively known as tauopathies—that are more rare. 

Some years ago, we discovered that pathological forms of tau cause the activation of a type of DNA called retrotransposons. This is another reason why I was really excited to come to Brown—a lot of work we've done in the retrotransposon biology and Alzheimer's disease area was based on what we learned from studies in aging biology led by John Sedivy and Stephen Helfand at Brown. I was thrilled to come where some of the original discoveries on retrotransposons and aging had been made that inspired our work. 

Retrotransposons are kind of similar to viruses. It's thought that they're present in the human genome because of viruses that inserted their DNA into our DNA over the course of evolution. There are certain areas of the genome that contain a high density of retrotransposons, but they are kept turned off because the DNA around them is very tightly wound up. Steve’s lab had shown that this type of condensed DNA becomes more open over the course of normal aging, which allows activation of retrotransposons. We had previously found that pathogenic forms of tau also cause DNA to become more open, and thought that this might drive retrotransposon activation. We are considering the possibility that tau-induced retrotransposon activation tricks the body into thinking that there is a viral infection when really it's just our own DNA. 

We tested an antiretroviral medication—an HIV drug originally approved in the 1990s—to see if it blocked the toxicity associated with retrotransposon activation. In lab models of tauopathy, we saw that it did. Since then, other labs have shown that this drug suppresses toxicity in mouse models, in cell culture models, and in brain organoid models of Alzheimer’s disease. We just finished a phase 2A clinical trial testing this drug in people with mild cognitive impairment due to suspected Alzheimer's disease. It's a small study, but we had nice results from the first phase of that trial. I'm now working with Ted and my previous collaborators to design and get funding for the next phase of that trial.

Dr. Huey, you do some research, but you're very firmly grounded in the clinical world and working with patients firsthand. How do you complement each other as the center's leaders?

Ted Huey, MD
Ted Huey, MD

TH: We're so happy to have Bess. It's been such a huge boost for the center and her expertise is so valued. And, as you point out, very complementary. We see patients at the Memory and Aging Program at Butler Hospital, and we do a lot of trials and observational studies. And we're happy to test treatments, but we're not going to develop them ourselves as we are a clinical program. We're reliant on basic and translational scientists like Bess to identify the promising therapeutic candidates that then can be tested. And when therapeutic candidates are identified, as a clinical research program we can tell them, are they safe? Are they efficacious? All of those kinds of questions. It's really great to have Bess and John Sedivy and other investigators—we're doing a trial for John as well—to give us the interesting compounds to then bring into patient populations.

BF: The academic science side of drug discovery is very exciting but can also be somewhat unfulfilling. You make some big discovery, you publish your findings, and it's like, hey everyone, this drug cures Alzheimer’s disease in mice! And you're hopeful that someone else on the clinical or pharmaceutical side might notice, make something of it, test it in patients, and develop a new therapy for Alzheimer’s disease. When scientists have a clinical partner, we can just move forward into patients, when appropriate, without waiting on someone else to do it. To have Ted's expertise here is going to really allow us to move things forward in that way. 

I never met anyone with Alzheimer's disease throughout my PhD and postdoctoral training. I was very much just in the lab, thinking about my own projects and my own science. But it's really important for basic scientists to interface with clinicians so that we actually interact with people affected by the diseases we study. When you think about people as people and talk with their caregivers and doctors, it gives basic scientists a different perspective. So I'm excited to work with Ted and have more interaction with patients in the community.

TH: I see patients clinically, and I don't see it as that different from the clinical research. With the research, you're taking it a next step and taking the things you observe in clinic and saying, oh, that's interesting. I wonder what might be causing that? Or, I wonder if a medication could make that better, or I wonder if we could measure that in a way that would actually provide more power for people to be able to detect medication effects or biomarkers? So there's no strict separation. And I, like Bess, really enjoy the dialogue with people doing other kinds of research. The projects I enjoy the most are ones where I feel like I'm really learning, when it's almost like a class. I have my piece of the project that I know and may have done before, but then I'm hearing about new approaches where I have to get out the books and read the papers, and that's an exciting process.

Dr. Huey, you study frontotemporal dementia, yet the center's name includes just “Alzheimer's disease”—which gets much more attention than other dementias. I wondered how this affects not only funding for research, but also diagnosis and clinical care for these other disorders.

TH: A question I'm very excited about is, what are these different pathologies that are causing dementia in a patient, and how do they each uniquely contribute to the phenotype of the patient we're seeing? People who have been studying FTD have been saying for years that there are a lot of these FTD proteins, like TDP-43, in the brains of patients who were diagnosed with Alzheimer's disease too. And now we're starting to appreciate that TDP-43 deposition is actually contributing to the symptoms of patients with Alzheimer’s disease. We're learning more and more that the most common type of dementia is mixed pathology, and it's actually pretty rare, especially for an older person, to have one single neuropathological process underlying their dementia. 

But we're still exploring the question of the tropism of these different pathologies. In other words, why do different neuropathologies target different regions of the brain? We’re entering a period in which we can examine the symptom presentation of patients with specific neuropathologies to be able to identify the clinical presentations associated with these specific neuropathologies. So even though I have studied FTD, my two current R01 NIH grants enroll patients with different diagnoses including Alzheimer's disease, FTD, Lewy body disease, and other neurodegenerative disorders. I'm interested in moving away from focusing on a single neuropathology and more towards understanding what the commonalities and differences are between these different degenerative processes.

Have any of the new drugs for early-stage Alzheimer's been tested in other dementias?

TH: They haven't. We do see a significant clinical effect with the anti-amyloid drugs [in Alzheimer’s]. We know they're very good at lowering amyloid, but there is this real question: why don't they do more clinically? One hypothesized answer to that—which I believe has some validity—is that the clinical efficacy of these medications may be limited by targeting just one of these multiple pathologies. So we are investigating the idea of giving these treatments in combination—i.e., personalized medicine—taking someone with different pathologies and making a treatment program that is personalized to them. That's what we do in cancer; we don't just say someone's got breast cancer, let's give them the breast cancer treatment. We characterize the biomarker profile of the cancer and target the treatment to that biomarker profile often using multiple treatments. We're hopefully going to move that way in dementia and neurodegenerative illness.

BF: Related to our recent clinical trial with the HIV drug, we want our research to be broadly relevant beyond Alzheimer's disease. That's part of the reason why we work on tau pathology: it's present not only in Alzheimer's disease, but in all these other neurodegenerative disorders as well. If we find something that helps decrease neurodegeneration as a consequence of tau, that drug, in theory, would be good for Alzheimer's as well as the wider group of neurodegenerative disorders that have tau pathology. In fact, this antiretroviral therapy approach has recently been tested in progressive supranuclear palsy, a type of tauopathy. The last phase of the trial had good results, suggesting that hitting this target might be broadly relevant for the larger group of tauopathies. Retrotransposons are actually also activated as a consequence of TDP-43, which is involved in certain types of ALS and frontotemporal dementias.

“ It's really important for basic scientists to interface with clinicians so that we actually interact with people affected by the diseases we study. When you think about people as people and talk with their caregivers and doctors, it gives basic scientists a different perspective. ”

Bess Frost, PhD

Could you see dementias and neurodegenerative disorders like ALS eventually being diagnosed on a continuum, like how autism spectrum disorder includes conditions once considered separate?

BF: Yes, Alzheimer's is defined by cognitive impairment and the presence of amyloid plaques and tau tangles in the brain, but it's actually pretty rare for a brain affected by Alzheimer’s disease to be clear of pathologies that are associated with other neurodegenerative diseases. So what even is Alzheimer's disease? It’s likely not as pure of a disease as has been historically characterized when you consider the neuropathology.

TH: It's funny you bring up ALS, because we now know ALS and FTD are often the same disease manifesting differently phenotypically, but with the same underlying neuropathology. More and more, the boundaries are getting blurred and mixed between different neurodegenerative illnesses.

Do you find some hope in the new Alzheimer's drugs, even though they are limited in who and what they treat? 

TH: Yes. The Alzheimer’s drugs are associated with slower progression of illness than if people don't get them. So that's a real watershed. We've never been able to do that before. And it does in some ways give hope for a lot of other mechanisms, because it shows that it is possible to improve the trajectory of patients by medication. It's really given a shot in the arm to the whole field.

BF: New discoveries over the past few years will allow for a disease diagnosis based on proteins present in patient blood samples. These blood biomarkers will allow us to confidently determine what disease patients have, what stage of disease they're in, and the degree of neurodegeneration or neuroinflammation in their brain. This is going to transform clinical trials in coming years, and potential treatment. It will change who we can enroll in a given study, our degree of confidence that they actually have the disease we think they have, and will allow us to see if the drug we are testing reduces neurodegeneration and neuroinflammation. Traditionally, these measures relied solely on cognitive testing, which can be more subjective, and brain imaging, which is very expensive.

Tell us about some of your plans for the center.

BF: Brown has a lot of people working in Alzheimer's disease and related dementias. I’m looking forward to working with investigators who are already at Brown, and recruiting new faculty to help to bridge the gap between basic science and the clinic. Not only from a personal interaction—the basic scientists interacting and learning with the clinicians and vice versa—but helping the basic scientists who have a drug target to move their work into the clinic when it's appropriate and feasible, and provide the training and infrastructure to make it happen.

TH: The other side of that is gratifying. I view myself fundamentally as a clinician and phenotyper—in other words, trying to very carefully say, how do these illnesses present? What are their symptoms? How does that reflect what's going on in their brains and their illness? And how can we measure possible changes in that? I like it when PhDs come to the clinic and can learn from people with these illnesses. I think it makes it very real and provides important information, perspective, and motivation.

How will the center collaborate with other local research groups, like the Alzheimer's Disease and Memory Disorders Center at Rhode Island Hospital?

BF: We really have strengths in Alzheimer’s disease and related dementias research and clinical care across the state. Ted and I are already working with clinicians and scientists throughout Rhode Island to coordinate our efforts to apply for designation as an National Institute on Aging-funded Alzheimer’s Disease Research Center. The size of the state makes it much easier to collaborate between institutions.

A big issue in clinical trials generally, but Alzheimer's and dementia in particular, is lack of participant diversity. How are you working to ensure that the center’s trials are representing the populations affected by these diseases?

BF: It’s often said that people from minoritized populations don't want to participate in clinical trials because of historical mistreatment, or people being tested upon who didn't agree to it. That is an oversimplification—there is actual research into why some people participate in clinical trials and others do not. Where you advertise and the design of the study are major factors. How demanding is the trial in terms of the number of clinic visits? Does the trial involve lumbar punctures? Tara Tang, the outreach manager for the Memory and Aging Program at Butler, knows a lot of this information. I was recently talking with her about our clinical trial design. Based on previous studies focused on participant enrollment, Tara can review a clinical protocol and point out certain elements that are going to decrease involvement of underrepresented individuals and can suggest tweaking certain things so that we are more likely to enroll a diverse cohort of participants. 

TH: And it's a little bit of a paradox, which is that you want to increase the diversity of participation in a particular trial—but the way not to do that is to just focus just on that trial. We’re getting the feedback that some of these communities are feeling a little frustrated by participating in a trial, and then the relationship ends when the trial ends. Tara does a great job of developing long-term and reciprocal relationships in our local communities, and integrating into the communities, so that it doesn't feel like we're coming into a community and saying, oh, we need 100 participants, and then you won’t hear from us again. Newer approaches are stressing the outreach work you put in and the connections you make before a particular trial is even conceived.

BF: There are some trials now that involve a board of caregivers and community members who weigh in on the design of the trial. The flow of information and expertise should go both ways. Listening to what the community needs and what they care about is very important.

Is there anything I didn't ask you about that you would like to add?

BF: I just really love Brown so far. The people I've interacted with are doing such interesting things, and they're so open and welcoming and generous with their time—not only for me, but also for the eight members of my lab who moved with me from Texas. My lab members have already begun to nicely integrate into the research community at Brown. I love Rhode Island in general. It's a really, really nice place to live.

TH: Yes, having come a year ago to Brown, I find it to be a very collaborative place. People work well together, which I think is just so necessary for these disorders that span multiple disciplines. It's really the special sauce Brown has that's going to make the Alzheimer's center very productive and valuable.