A research priority and a family’s heartbreak.
Alzheimer’s Disease is a progressive neurological disorder affecting millions of Americans, most of whom are not yet diagnosed. It slowly destroys memory and thinking skills, leaving the patient unable to manage basic daily tasks without considerable support. It is the sixth leading cause of death in the United States, but the National Institute on Aging (NIA) said current estimates suggest it might actually be third after heart disease and cancer.
The chances of developing AD are not equal and are quite complicated. Older age does not cause AD, but advancing age, specifically for late-onset disease, is the most common form. Early-onset AD occurs in less than 10 percent of cases, typically between ages 30 to mid-60s. It is often linked to an inherited change in one of three genes. AD can run in families, though a family history is not necessary to develop the disease.
Other AD risk factors are modifiable. Smoking, poor diet, high blood pressure and low physical activity have all been associated with a heightened risk. Some populations and demographics are hit harder than others, though existing research and data is far from comprehensive and equitable.
The complexity of AD has long stymied a full understanding of the condition, not to mention discovery of any preventive or curative remedies, but scientists remain undaunted. Too much—and too many people—remain at risk.
“The more we learn, the more questions we have and the more uncertainty. The trick is to not let the uncertainty hinder us and to keep integrating the pieces of the puzzle of Alzheimer’s disease,” says neurologist Howard Feldman, MD, director of the Alzheimer’s Disease Cooperative Study (ADCS).
Collaborative Efforts
The ADCS is part of a larger effort at UC San Diego that includes the Shiley-Marcos Alzheimer’s Disease Research Center (ADRC) and the Brain Health and Memory Disorders Clinic at UC San Diego Health. Feldman’s arrival in 2016 signaled a shift in focus away from massive, monumental studies and trials that have, so far, not produced a singularly effective treatment. Instead, efforts have focused on smaller, more nimble efforts with sharpened targets that may, at the very least, answer some questions and produce measurable progress, quickly and efficiently.
“We strive to keep focused on the highest-quality research and how we set achievable research goals that answer important questions with approaches that will make a difference in the lives of our patients,” Feldman says. “You might not reach all of the goals on schedule, but each step successfully contributed helps move us closer.”
Currently, the ADCS is involved in eight clinical trials, including investigations into whether different drugs can protect or improve memory and the therapeutic benefit of exercise on cognition. It has completed 10 other trials. ADCS scientists have published more than 200 related papers. They are also developing HALT AD (short for Healthy Actions and Lifestyles to Avoid Dementia), a novel online brain health platform that will help persons lower their risk factors for AD before disease manifests.
“You would be hard-pressed to find another place that has devoted more brainpower and brilliance to solving the enigma that is Alzheimer’s,” says UC San Diego Chancellor Pradeep K. Khosla. “Across the spectrum, from basic science to clinical care, our scientists and physicians have grappled with the challenge like few other institutions. We won’t stop until we, in collaboration with others, can claim true and complete success.”
In January 2022, UC San Diego and the University of Southern California (USC) announced a $50 million gift from the Epstein Family Foundation to expand and accelerate development of effective treatments for AD, and perhaps find a cure or preventive.
The gift was inspired, in part, by Daniel Epstein’s identical twin brother, who had suffered from AD for 15 years and died due to related complications. Epstein, a USC alumnus, and his wife, Phyllis, are longtime philanthropic supporters of both universities. The Epsteins believe the two universities can combine resources and expertise to achieve exponential results.
“When researchers are interacting and sharing ideas, it can lead to new solutions that they might not have originally thought about,” says Daniel Epstein. “When two stellar universities are working together to achieve the same goal, great things will come out of it.”
USC will focus its funding on support for improved neuroimaging, informatics and clinical trials. And at UC San Diego, the gift will help to advance the potential of gene therapy as either a treatment or preventive for AD and investigate existing or repurposed drugs and natural products that might treat AD.
Mending Genes
Gene therapy is not a new concept. It dates back to the 1960s. The basic idea involves transplanting normal genes into cells to replace missing or defective ones to correct genetic disorders. It is being tested for a wide range of diseases, including cancer, cystic fibrosis, heart disease, diabetes, hemophilia, AIDS and some neurological conditions. It holds the potential to be curative.
The Alzheimer’s gene therapy program at USC and UC San Diego will look at treating families with mutations in genes coding for proteins linked to a higher risk of AD, such as over-production of plaques in the brain that initiate a cascade of processes resulting in cell death, cognitive decline and eventual dementia.
For more than two decades, Mark Tuszynski, MD, PhD ’91, UC San Diego professor of neurosciences, and colleagues have been investigating the potential of gene therapy for AD in a different way.
In 2001, Tuszynski conducted a novel phase I clinical trial to assess whether injecting nerve growth factor into the brains of patients diagnosed with AD might slow or reverse neuronal degeneration. That seminal work led to last year’s announcement of a new, first-in-humans clinical trial to assess the safety and efficacy of delivering a specific protein called brain-derived neurotrophic factor (BDNF) into the brains of patients with AD or Mild Cognitive Impairment. BDNF is part of a family of growth factors found in the brain and central nervous system that support the survival of existing neurons and promote the growth and differentiation of new neurons and synapses. BDNF is particularly important in regions of the brain susceptible to AD degeneration.
“It has required decades of focused work to get to this point, but we’ve found in animal studies that delivering BDNF to the parts of the brain that are affected earliest in Alzheimer’s disease results in reversal of loss of neuronal connections and protects against ongoing cell loss,” says Tuszynski, who also serves as director of the Translational Neuroscience Institute at UC San Diego School of Medicine.
Repurposed Drugs
The search for brand-new treatments for AD has yet to produce a major success story. Consequently, many researchers have turned to looking anew for potential remedies already in their armamentarium.
The second effort funded by the Epstein gift is dubbed Powder for Pennies, or P4P. It will ask whether drugs already approved or developed for other conditions may also benefit persons with AD. The recent case of bumetanide provides an example. This treatment is an oral diuretic or “water pill” used to ease congestive heart failure by reducing fluid retention, but bumetanide has also been found to reverse abnormal expression of a gene already identified as a strong risk factor for sporadic or late-onset AD.
Thus, an older drug might be brought through clinical trials quite quickly and, if successful, could provide an affordable and widely available new treatment possibility for AD.
The P4P program will also develop and implement early-phase “SMART” clinical trials with an expedited assessment of the potential of existing drugs and compounds. It will further leverage ADCS’s existing network of labs and collaborators and their deep expertise in conducting early trials of candidate treatments. Once compounds of promise are identified, they could be sent to USC for larger-scale phase III trials.
Finding a Cure
“It’s instructive to step back and ponder how UC San Diego is frequently front and center for the most seminal discoveries in Alzheimer’s disease,” says James Brewer, MD, PhD, chair of the Department of Neurosciences and director of the ADRC. “Not all of these discoveries were acclaimed at the time as groundbreaking or fundamentally changed thinking, but over time, they endured scientific scrutiny, were built upon by others, and finally became widely recognized as breakthroughs critical for advancing the fight.”
Brewer is cognizant of the long road ahead, however. It’s a fight with no end in sight. But he is also optimistic that the work here, supported by philanthropy, will make a difference.
“I have no doubt the path to a cure passes through UC San Diego.”
—Scott LaFee is director of communications and media relations for UC San Diego Health.