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?
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?
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.