*This is part of UF Explore magazine’s CSI: Alzheimer’s. Click here to read the full story or listen above.
By Michelle Koidin Jaffee
Growing up in the foothills of the Bavarian Alps, Stefan Prokop imagined he would follow in the footsteps of his father, a homicide detective. Prokop’s interest in analyzing evidence and solving mysteries led him to forensic pathology and, during medical school, into the lab of a prominent researcher in Alzheimer’s disease.
“From Day One, I was just fascinated by the specific question of Alzheimer’s disease,” he says. “I just walked in and said, ‘That’s what I want to do.’”
Twenty years later, Prokop stands beneath fluorescent lights in a UF Health lab, a donated brain on the stainless-steel table before him and four medical residents leaning in to see. Now director of the UF Neuromedicine Human Brain and Tissue Bank, Prokop describes telltale signs of Alzheimer’s, such as shrinkage in the frontal lobe and other regions, as he dissects the brain.
A leader in the field of neuropathology, Prokop is among dozens of investigators at the University of Florida hunting for the keys to Alzheimer’s disease, a progressively disabling disorder that afflicts more than 6 million Americans over age 65. That number is projected to grow to 12.7 million by 2050, according to the Alzheimer’s Association. In Florida alone, about 580,000 people currently live with Alzheimer’s, and in just the next five years that number is expected to grow to 720,000.
People with Alzheimer’s slowly lose the ability to handle daily tasks. Beyond memory loss and confusion, they have increasing difficulty with navigation, grocery shopping, bill paying, self-care such as dressing and bathing, motivation, balance and, in late stages, walking and swallowing.
Current treatment options are limited. Some people see temporary improvement in cognitive function and memory using medications, but these do not stop the disease from progressing. The cost in unpaid dementia caregiving by family and friends was valued by the Alzheimer’s Association at $256.7 billion in 2020.
Examining brain segments under the microscope, Prokop seeks to understand which of the molecular and cellular changes related to Alzheimer’s that he sees are a cause of the disease — and which could be a result of it. He is particularly focused on the two main Alzheimer’s-related brain changes: a protein called beta-amyloid that clumps into plaques between neurons and a protein called tau that abnormally accumulates inside neurons to form tangled threads known as neurofibrillary tangles.
Prokop, who was recruited from the University of Pennsylvania in 2019 as the first Fixel Scholar of the new Norman Fixel Institute for Neurological Diseases at UF Health, is investigating how these plaques and tangles interact and damage the brain.
Like a good detective, he is coming at it from multiple directions.
Under a new National Institutes of Health grant, he and UF neuroscientists Todd Golde and Yona Levites are exploring a large number of proteins believed to accumulate alongside amyloid — looking simultaneously at their role in donated human brains and mouse models to reveal any possible correlation with severity of Alzheimer’s symptoms. Early data suggest many of these could be key players in Alzheimer’s disease and potential new targets for intervention.
Prokop is also collaborating with UF neurogeneticist Matt Farrer to sequence the genomes of donated brains. This could help identify protective gene variants, for example in a person who had significant Alzheimer’s pathology at autopsy but never had dementia in life.
To Prokop, one way to better understand Alzheimer’s is to examine brains from diverse racial backgrounds, as most published research on the disease involves white people of European ancestry. In his role as leader of the neuropathology core of the 1Florida Alzheimer’s Disease Research Center — a UF-led consortium of top research institutions known as the 1Florida ADRC — he is working to spread the word and encourage people of diverse racial backgrounds to make arrangements for future brain donation.
“In the end, we want to treat the population,” Prokop says. “We don’t want to treat one subgroup of the population, so what we hope to gain from our research is better insight: Are these genetically diverse populations similar, or have we studied one type of Alzheimer’s disease that occurs in Caucasians, and is the disease different?”
The 1Florida ADRC, funded by the National Institute on Aging, enrolls research participants with and without memory disorders and tracks them for years to reveal factors that influence progression rates, using blood samples, cognitive testing and state-of-the-art brain imaging. Some enrollees also participate in clinical trials to test potential new medicines.
One focus that distinguishes the 1Florida ADRC from more than 30 other such Alzheimer’s Disease Research Centers in the country is that over 60% of participants are Hispanic.
“We’re hoping to make a major contribution to understanding Alzheimer’s disease by understanding how it impacts diverse populations differently,” says Golde, director of UF’s McKnight Brain Institute and principal investigator of the 1Florida ADRC, which is a collaboration of over 40 researchers from UF, Mount Sinai Medical Center in Miami Beach, the University of Miami, Florida Atlantic University and Florida International University.
The clinical arm of the 1Florida ADRC is tracking up to 600 study participants, who are undergoing testing in a five-year, $15 million project.
Artificial intelligence will be used to combine all the data — behavioral, clinical, biological and advanced neuroimaging biomarkers — to predict future development of Alzheimer’s, says UF neuroscientist David Vaillancourt, who leads the biomarker core for the study. The data will be available to Alzheimer’s researchers nationwide.
The focus on diversity extends to those who study the disease. Valerie Joers and Karina Alviña are the first two scholars selected for the new “AlzSTARS” program, which recruits and trains junior investigators from diverse racial, ethnic and gender backgrounds, as well as diverse locations and research interests.
Golde, an internationally known expert in the scientific understanding of Alzheimer’s, describes the field’s 30-year pursuit as “humbling.” Initial excitement over the first discoveries of Alzheimer’s-related brain changes led to many trials of therapies that, despite sound scientific basis, have failed to alter the course of the disease. But with incremental successes in the lab, recent increases in federal and state funding, the passion of up-and-coming young researchers and knowledge gained from past failures, he sees a future in which Alzheimer’s can be both treated and prevented.
“I’m optimistic that we’re going to get there, but it’s going to take some time,” he says. “It’s not going to be necessarily a linear path with one success after another. But we have learned enough from our failures that we’re going to have new approaches.”
One place where those new approaches are evident is at UF’s Center for Translational Research in Neurodegenerative Disease, where neuroscientists are creating new tools, like unique mouse models.
“At UF, we have some of the best basic science modelers, who have devised mouse models that are widely used throughout the world,” says Steven T. DeKosky, an internationally renowned neurologist honored in 2020 with the Alzheimer’s Association’s Henry Wisniewski Lifetime Achievement Award.
“These models are yielding new insights into one of the big unanswered questions: How does beta-amyloid talk to tau?” Golde adds. “We know that amyloid pathology precedes tau in neurodegeneration and nobody understands the link, but we think that these novel mouse models are beginning to more faithfully reproduce that crosstalk and may give us insights.”
UF neuroscientist Jada Lewis, in collaboration with investigators at the University of Minnesota and Harvard, has developed mice that express human tau that can be turned on and off like a light switch using the antibiotic doxycycline. This model has been cited in over 1,300 research papers, according to the database Web of Science.
“Mouse models are yet another tool in the arsenal of fighting against Alzheimer’s disease,” says Lewis, deputy director of the McKnight Brain Institute. “We exhaust every possibility we can through cell models, because it preserves animal use and it’s quicker and often cheaper. But there are some things you can’t model in cell culture or on the computer, and that’s the actual interaction between tau and amyloid pathologies and resultant behavioral problems.”
With funding from the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, Lewis is working with fellow UF neuroscientist David Borchelt to produce new strains of mice that model the amyloid and tau pathologies characteristic of human Alzheimer’s disease. Their newest models should significantly reduce the number of mice that researchers have to use in many of these complex studies, Lewis says.
“In general, the field thinks that amyloid comes first and then tau is downstream of that,” Lewis says. “But there’s also another school of thought that tau may come first and interact with amyloid in that manner.”
Pinpointing the timing could be instrumental in developing new treatments that interrupt the disease.
Lewis and Borchelt are investigating what happens when tau pathology is turned on first and, conversely, what happens when amyloid pathology is turned on first. They seek to answer the question: How does the timing affect the formation of global amyloid pathology often seen in Alzheimer’s disease patients?
“We know there’s a connection between the amyloid pathology and the tau pathology,” says Borchelt. “If you have amyloid, tau pathology seems to be worse — more severe or perhaps in different locations. What we’re trying to understand is the connection between those two.”
In addition to modeling, Lewis’ other main focus is on training the next generation of researchers who will take on the complexity of Alzheimer’s and related dementias. She and two other UF scientists lead an NIH program to train postdoctoral fellows in clinical translational research in Alzheimer’s disease.
“The more people we get looking at it in different directions,” she says, “the better we’ll be able to describe the disease and attack the disease.”