Long before Dr. David Holtzman became a renowned national authority on Alzheimer’s disease research and memory disorders, studying the brain was at the forefront of his mind. The field attracted him from the start as a medical student at Northwestern University in the early 1980s for one fundamental reason.
“In 1982, I was in a class that was really focusing on human neurological diseases, including Alzheimer’s, and what became quickly apparent was that this is one of the most impactful diseases – and we knew virtually nothing about it,” said Dr. Holtzman, scientific director of the Hope Center for Neurological Disorders and director of the Knight Alzheimer’s Disease Research Center at Washington University in St. Louis, Missouri. He will the keynote speaker at USF Health Research Day on Friday, March 1.
“I thought, ‘How can this be? We were already starting to have breakthroughs in different types of cancer and heart disease. And here was this disease that robs somebody of their life and what it means to be a human, yet we didn’t know what was going on. I felt we needed to understand more about it to make an impact, and that’s the biggest reason I was drawn to the field.”
Dr. Holtzman’s path as a preeminent researcher of brain diseases unfolded in somewhat atypical fashion. He was in a six-year medical program, meaning he went right from high school through an abbreviated undergraduate experience at Northwestern University, graduating in 1983, and then directly into Northwestern’s medical school, where he earned his MD in 1985.
“I was young when I graduated from medical school and I thought, ‘I really like research,” he explained. Knowing he intended to pursue neurology, Dr. Holtzman proceeded to get his clinical training with a residency at the University of California-San Francisco (UCSF) from 1985-89, followed by his post-doctoral research there from 1989-94. But during that time, he gained invaluable training in a lab setting.
“The big breakthrough for me was that I realized some of the best molecular and cellular science at that time was being done in labs that studied the development of the brain,” he said. “There really weren’t many labs working on diseases of the aging brain at the time. And even though I knew I ultimately wanted to work on neuro-degenerative disease and Alzheimer’s, I felt it was important to be in a strong cellular and molecular lab to get great training.”
During his post-doctoral work, an Alzheimer’s breakthrough emerged in 1993, finding that the APOE gene – involved in making a protein that helps carry cholesterol and other kinds of fat in the bloodstream – was a major risk factor in the disease.
“Today there are many other genetic risk factors that have been discovered, but this was the first – and also the most powerful genetic risk factor,” he said. “I became really fascinated and read everything I could about it. And after that, I moved into my own laboratory and wound up focusing a lot of my career working on that.”
Beyond his research at UCSF, Dr. Holtzman founded a memory disorders clinic to see patients with neurological conditions. “I was already neurologist then,” he said, “but I was spending about 80 percent of my time in the lab in addition to clinical work.”
In 1994, he moved to Washington University in St. Louis as an assistant professor and to start the Holtzman Lab as well as to do clinical work. He has remained at Washington University ever since, serving as a professor of neurology, chair of the Department of Neurology from 2003-21, director of the Knight Alzheimer’s Disease Research Center at the Washington University School of Medicine, and scientific director of the Hope Center for Neurological Disorders.
“The idea of of the Hope Center was to stimulate research more quickly with pilot grants every year and also provide core facilities,” he said. “We could really help get things done much faster. It’s already been 21 years since we launched the Center, and it’s continued to grow – we now have about 170 lab principal investigators, and we give out at least four grants each year.”
His lab boasts many accomplishments, such as showing how the APOE gene contributes to Alzheimer’s; the development of a method to measure protein synthesis and clearance in the central nervous system of animals and humans; the development of CSF and plasma biomarkers for Alzheimer’s disease; and much more.
Dr. Holtzman has received numerous honors for his work, including a Paul Beeson Physician Faculty Scholar award in aging research, the Potamkin prize from the American Academy of Neurology for research on Alzheimer’s, the MetLife award for his Alzheimer’s research, and the Rainwater Prize for Outstanding Innovation in Neurodegenerative Research. He is an elected fellow of the National Academy of Medicine of the National Academy of Sciences.
He is also past president of the American Neurological Association and has trained more than 70 graduate students, post-doctoral fellows and physician-scientists, many of whom have gone on to successful careers in academia and industry. And he continues to make steps forward in the understanding of Alzheimer’s through state-of-the-art research.
What aspect of that research does he find most promising now?
“In most neurodegenerative diseases, Alzheimer’s being one, there are disorders of protein aggregation, where certain proteins clump up,” Dr. Holtzman said. “And when that happens, they lead to damage in the brain. With Alzheimer’s, there are two proteins where that happens – one is called amyloid and the other is called tau. And when they build up, there’s an inflammatory response in the brain. We know that all three of those factors are important in the disease, and right now we’re studying how they are interacting and trying to better understand that.”
In an era where science and facts are often under assault, Dr. Holtzman believes that bringing new talent into research – regardless of the subject matter – is of vital importance.
“Science is really all about trying to understand basic truths in the world – how things work,” he said. “And it leads to good outcomes, such as potential treatment of diseases. The problem now is when you have certain countries over the last many years – and more so now in the United States than ever before – where you have people not following scientific truths. The U.S. has always been a leader in scientific discovery. When you get away from that, it threatens the ability of the country to continue to be a leader in doing good things for people.”
His message to students on the value of research is a simple one.
“Doing the most rigorous science, you may not be successful every time – in fact, 95 percent of the time when you do research, things may not work,” Dr. Holtzman said. “But when they do, it truly gives you fundamental insights that are translated into major new therapies we’re utilizing. And that is finally coming to fruition for a number of neurological diseases. When I was training, there was virtually nothing anyone could do. But the entire field has changed. And it is really due to basic research.”