“When it comes to clinical trials, I can always tell you more about what cannot be done than about what’s going to go forward,” says Martin Sadowski, MD, PhD. “And that is the challenge: how are we going to advance Alzheimer’s care despite all these barriers?”
Dr. Sadowski’s career could be described as a long, unrelenting effort to answer this question. He is professor of neurology, psychiatry, biochemistry and molecular pharmacology at NYU Grossman School of Medicine, where he has also been appointed as the inaugural Zachary and Elizabeth M. Fisher Professor in Neurodegeneration and Alzheimer’s Disease. He co-directs the Zachary and Elizabeth M. Fisher Alzheimer’s Disease Education and Research Program, and in 2024 he became the founding director of the Fisher Center Alzheimer’s Clinical Trials Program at NYU Langone Health.
A physician-scientist with decades of experience at the intersection of research and patient care, Dr. Sadowski brings a uniquely well-rounded perspective to one of today’s most urgent medical problems: developing new Alzheimer’s treatments while ensuring they reach the patients who need them most.
In this conversation, Dr. Sadowski reflects on his journey from neurosurgery to neurology, the evolution of his research agenda through his clinical practice, as well as his vision for an approach to clinical trials that may help bridge the gap between drug development and the treatment options that are available to patients.
FROM BRAIN MAPPING TO ALZHEIMER’S CARE
How did you first become interested in Alzheimer’s disease?
I had an interest in neuroscience from very early on. I was initially trained through an MD/PhD program at the Medical University of Gdansk, in Poland, and one of my projects involved performing neurosurgery on rats. We were mapping brain connections, and for that I had to study brain anatomy in many different animals, laying a foundation that later allowed me to focus on clinical research.
Alzheimer’s entered the picture as we tried to understand how different areas of the brain develop the disease differently. There are some areas in the human brain that are severely affected from very early on—by the time a person dies, there’s almost no nerve cell left. But there are other areas, sometimes very close by, that remain relatively intact. And we don’t know why this happens.
To look into this, you need to understand where a given brain area functionally starts and ends—you need to establish clear anatomical underpinnings for the study of disease progression. So I did a postdoc to work on this problem, familiarized myself with Alzheimer’s research, and then from there I went into clinical training and became a neurologist, because I wanted to continue taking care of patients with Alzheimer’s disease.
How did you become involved with clinical trials?
I’ve been involved with the Clinical Trials and Research Studies Program at NYU since 2008, and I worked closely with Dr. Steven Ferris, who established the program. It’s one of the oldest clinical trial programs in the United States and has been in continuous operation since 1990. There is no Alzheimer’s drug approved by the FDA that we have not participated in developing.
As principal investigator, I have been heavily involved in about 45 clinical trials of various therapies for Alzheimer’s disease. We have a pretty busy portfolio of industry-sponsored trials—the typical clinical trial model, where a company has an idea for a drug, asks us to recruit patients, design and run the trial, and then analyze the data to determine the drug’s efficacy.
THE FISHER CENTER ALZHEIMER’S CLINICAL TRIALS PROGRAM
How did that work lead to the partnership with the Fisher Center Foundation?
The idea started with an email I received from the Foundation last year, in July, after the FDA approved the new anti-amyloid drug Kisunla for therapeutic use. I was involved in one of the main clinical trials for Kisunla, so the Wall Street Journal interviewed me for an article—and that led to a conversation with the Fisher Center Foundation about creating a program to approach clinical trials in a new way.
It’s important to understand that drug development is an extremely expensive endeavor. If a pharmaceutical company approaches me, I can take a new drug from the lab to FDA approval right now. But designing trials, enrolling patients, reviewing the results—the price for this is $1.5 billion. That’s the cost of the drug.
As a result, if you imagine a pie chart, three-quarters of it would be industry-sponsored trials aimed at getting new Alzheimer’s drugs approved by the FDA for general market use. Only one quarter would be investigator-initiated trials—that is, studies ideated by clinicians, like me, who want to explore specific use cases for drugs that have already been approved. So, the idea was to create a program to bridge this gap between drug development and patient care.
How does the new program help to address this gap?
When it comes to clinical trials, I can always tell you more about what cannot be done than about what’s going to go forward. And that is the challenge: how are we going to advance Alzheimer’s care despite all these barriers? The gap is big, everyone understands that. But the question is, how are we going to bridge this big gap?
I had many ideas for what could be done once I was no longer working to provide specific data to the FDA. For example, you could administer drugs that have already been approved to people with presymptomatic disease and potentially prevent the disease from happening. You could take a drug that hasn’t worked in monotherapy and try it in a combination therapy. You could compare how different subpopulations of patients respond to treatment.
The possibilities would take hours to list, once you start thinking about all the potential applications that deserve to be explored. And now, thanks to the involvement of the Fisher Center Foundation, it’s like when someone thought of investing in developing of integrated circuits—and a few years later you had Intel and a few years after that you have Nvidia.
BEDSIDE TO BENCH—AND BACK
Where do you see the program going in the next few years?
We currently have 18 active Alzheimer’s clinical trials and 10 more in start-up phase at NYU. The Fisher Center Foundation is a major force behind this expansion, because of its willingness to support high-risk, high-reward projects that require some kind of proof-of-concept before we can approach large funding institutions, like the NIH.
While the Foundation has been extremely generous, investments on the scale of billions of dollars, as I mentioned, obviously require the involvement of multiple stakeholders. So, we consider this our pilot initiative, which might attract more support for this kind of research from the pharmaceutical industry, the NIH and other big investors. We have been very successful with this approach in the past, when the Foundation helped my research team secure two major NIH grants for projects exploring the therapeutic potential of glial cells in Alzheimer’s.
At present, the Foundation’s support gives us spending flexibility to optimize our efforts with respect to three things: the impact of new trials for patients, the awareness that each trial generates with investors, and the costs. Over time, it is even possible that the program will evolve into a platform for broader collaborations—say, if a laboratory at The Rockefeller University has a molecule that shows promising therapeutic potential, we would be able to help them test a drug developed from that molecule.
How does the clinical trials program complement your work in translational research?
My research has always worked in tandem with my clinical work, and benefitted enormously from it. The typical thing is to do something in the lab and then see how it might be used to help patients, but my team and I take the reverse approach—working from the bedside to the bench, and then from the bench to the bedside. This creates a powerful feedback loop where clinical experience informs lab discovery, which then in turn suggests new strategies for clinical treatment.
For example, we’re currently working on project to adapt chimeric antigen receptor therapy from cancer treatment, to address key limitations of Alzheimer’s treatment highlighted by our clinical work. Conventional antibody infusions are expensive, require lengthy administration times, and often trigger brain inflammation—whereas this new approach would be designed to target and remove amyloid-beta plaques while minimizing adverse reactions from the patient’s immune system.
Challenges like these can only be addressed by going back to the bench, getting to the root of the problem and designing experiments to solve it. But when you start from the bedside, working with patients, you know ahead of everyone in the lab what the issue is. You don’t need to find a purpose, because your research began with it. You can formulate much better questions, and always work your way to the answers with your patients’ best interest in mind.
In this line of work, you’re going to hear about a lot of struggle—it’s never going to be peaches and cream. But I think people are increasingly aware that it’s a struggle with a real purpose, which eventually touches each and every one of us. Every trial we design, every drug we test, brings us one step closer to understanding not just how to treat Alzheimer’s, but how to prevent it. And in a disease where time is the most precious commodity, that is the most urgent mission of all.
