Deep in the mountainous Antioquia region of Colombia in the 1980s, clinical researchers led by renowned neuroscientist Francisco Lopera made a remarkable discovery.
One family carried a rare genetic mutation that causes a unique, early-onset form of Alzheimer’s disease with near certainty — essentially guaranteeing development of the condition by age 45.
The mutation — known as PSEN1 E280A but referred to by locals as “La Bobera” — was aggressive, early, and nearly unavoidable.
For researchers, this was extraordinarily rare: a living population in which the cause of Alzheimer’s was known and predictable. On its own, it was one of the most significant findings in Alzheimer’s research.
Then came an even more unexpected discovery.
Within that same family, a handful of individuals carried the same devastating mutation but showed almost no cognitive decline.
Their brains mirrored the family’s pathological profile, containing the sticky amyloid and tau proteins that destroy neural connections over decades. Yet these individuals remained cognitively intact well beyond their genetic timeline.
After decades of investigation, researchers in 2019 and 2023 traced that protection to two naturally occurring genetic variants: APOE3 Christchurch (APOE3Ch) and RELN-COLBOS.
Remarkably, these variants developed in human patients without any laboratory intervention and provided nearly 30 years of cognitive protection against one of the most aggressive forms of Alzheimer’s disease known to science.
One of the researchers behind these recent discoveries is Claudia Marino, PhD. An assistant professor of neurology at The University of Texas Medical Branch (UTMB), Marino works at the Sealy Institute for Drug Discovery.
Today, her work at UTMB is guided by one question: How can we protect against Alzheimer’s disease?
Armed with recent multiyear philanthropic support, the answer she is pursuing has the potential to shift how we think about Alzheimer’s disease — from one that is treated to one that might be prevented.
A season of suffering and serendipity
In 2011, Marino was a master’s student in Italy, searching for a thesis topic. Around the same time, her close friend’s father had just been hospitalized with a severe form of Alzheimer’s disease. It was aggressive and had few effective treatment options.
Witnessing the suffering and stress caused by Alzheimer’s, Marino set her sights on making a difference in the battle against this destructive disease.
Then, serendipity struck.
“I was hoping I could be involved in research that was supporting this type of work,” Marino said. “The serendipity was that my thesis mentor offered me the opportunity to test some small molecules designed to help against Alzheimer’s disease. Since then, I have become so passionate that I wanted to stay in this field because I thought there was a really important need to find therapies.”
That moment of serendipity has sustained Marino for more than 15 years. Her training moved from biophysical chemistry in Italy to a joint PhD program between UTMB and the University of Palermo, where she investigated the biological properties of protective proteins.
She then conducted a postdoctoral fellowship at Harvard Medical School’s Schepens Eye Research Institute under Joseph F. Arboleda-Velasquez, PhD, an internationally recognized scientist and associate professor of ophthalmology. There, the goal was to convert the protective genetic variants found in Colombian patients into possible therapies.
During this fellowship, Dr. Marino made significant contributions to two landmark findings that identified APOE3Ch and RELN-COLBOS as naturally occurring genetic variants capable of protecting the brain against Alzheimer’s disease.
She now leads her own laboratory at UTMB, weaving together every thread of training and personal experience into an ambitious research program.
More than memory loss
For most people, Alzheimer’s disease means memory loss. For Marino, that statement is true but incomplete.
“Memory loss, or dementia, is really the very final phase of a disease that started about 20 years earlier,” she said.
Inside the brain, specific proteins — amyloid and tau — become altered. This causes them to become sticky and group into deposits that attack neurons and disrupt the synaptic connections that allow us not only to remember, but also think, speak, and function.
By the time a patient walks into a clinic with memory problems, the damage has often been accumulating for decades.
“Most of the time, it’s already too late. All the damage is there,” she says. “And on the other side, we are still facing the challenge of targeting the proper cause. That’s why it’s so complex.”
The current treatment landscape reflects that complexity. Most FDA-approved interventions address symptoms rather than the underlying disease process.
A handful of newer antibody therapies show modest effects on some of the disease’s causes, which is encouraging. However, not all patients are eligible because of the risk of serious side effects.
More than 120 years since Alzheimer’s disease was first described in 1906, there is still no cure.
“We simply act too late,” Marino said plainly. “The therapies don't always work, and the effects are not always very strong. We need more.”
A new path to the brain
What Marino is building at UTMB is a system for delivering the same protective genetic variants found in those Colombian patients directly to brain cells in people with Alzheimer’s disease.
The challenge, however, is not just identifying the right genes, but getting them where they need to go.
The brain is separated from the rest of the body by the blood-brain barrier. This protective mechanism keeps harmful substances out of the brain but also blocks most therapeutic agents from reaching the neurons that need them.
Standard gene therapy approaches use viral delivery systems that carry significant risks and limitations, including size constraints and the potential for immune responses.
Marino is working with a novel technology called the mini-nucleosome. This patented, nonviral delivery cargo, developed by AAVINUE Inc., can effectively carry genetic material across the blood-brain barrier, with early evidence of strong stability and no observed toxicity in animal models.
Unlike viral approaches, there is no size limit on what it can carry. And unlike monthly injection regimens, preliminary data suggests it remains stable for more than a year.
“It’s a delivery of a gene, and it’s known as less risky than the current gene therapy approaches,” she said. “It can reach the brain, which is another important limitation of curing brain diseases, and it’s stable.”
“Almost like a vaccine, patients would no longer be as susceptible.”
Sanja Sever, PhD, professor and vice president of drug discovery at UTMB, sees the same potential.
“Dr. Marino’s investigation will not only advance fundamental knowledge, but also holds significant potential to redefine how we approach therapeutic options for neurodegenerative diseases,” she said.
Agenor Limon, PhD, associate professor of neurology and director of the UTMB Mitchell Center for Neurodegenerative Diseases, expands on the significance of this project.
“What makes Dr. Marino’s research especially exciting,” he said, “is its translational potential. Her work aims to leverage these naturally protective pathways to develop therapeutic strategies that could mimic or enhance these resilience mechanisms in individuals vulnerable to Alzheimer’s disease. This approach could open entirely new avenues for precision therapeutics in neurodegenerative disease.”
The goal is not merely treatment, but protection. If the mini-nucleosome can successfully deliver the protective genetic variants to brain cells, and if those variants offer the same protection observed in Colombian patients, the result would function more like a vaccine than a conventional therapy.
Patients would receive the genetic material and, in theory, become significantly less susceptible to the disease process that eventually leads to dementia.
The disease in a dish
One of the most significant advances in Marino’s research pipeline is the use of patient-derived induced pluripotent stem cells (iPSCs), made possible at UTMB through the support of the Moody Brain Health Institute. This is a technology that has only recently matured enough to make this kind of research possible.
From skin or blood cells donated by patients, researchers can reprogram those cells into any cell type needed for study, including neurons and the supporting cells of the brain.
The result is neurons that carry the full genetic and biological history of the patient who donated them, including the factors that may be contributing to Alzheimer’s disease pathology, without the need for invasive brain biopsies.
“We can recreate, in a dish, cells that have a patient’s history,” Marino said. “If a patient is diagnosed with Alzheimer’s, we can capture those genetic factors in a dish and assess whether our delivery system can successfully rescue those phenotypes.”
This system runs in parallel with animal models, allowing researchers to study how a therapy distributes throughout the body and reaches the brain. Together, these approaches provide a more robust picture of whether the mini-nucleosome system is working and what areas need to be optimized before clinical trials can become a realistic next step.
The bridge philanthropy builds
Marino began her independent career as a principal investigator at UTMB just one and a half years ago. She is building her laboratory, her team, and her research pipeline at the same time. This phase of a scientific career requires exactly the kind of flexible, risk-tolerant investment that federal funding rarely provides.
Multiyear philanthropic support from the JSRM Foundation has made this project possible, and for Marino, the significance extends beyond the resources.
“This was, honestly, a dream come true,” she said. “I’m a junior investigator, so I really benefit from support for high-risk, high-reward projects.”
“Federal funding requires very strong data and very solid foundations,” she continued. “Philanthropic support is allowing me to bridge that gap.”
Federal grants are essential for scientific research, but they usually require strong existing evidence, a proven track record, and proposals that closely follow established funding requirements.
Philanthropic support operates differently. It can take a chance on a hypothesis that is theoretically strong but still in early stages of testing. It can back a scientist who has the training and vision but not yet the publication record needed to compete for a major federal award.
“Philanthropic support is allowing me to obtain all of the necessary data and experimental outcomes that can give a much more solid foundation of the overall research mission,” she said. “And then, of course, it will allow me to make a stronger proposal that can be submitted to federal funding.”
In this way, philanthropy is a bridge, as she calls it, between a promising idea and the institutional support required to make it a clinical reality.
A world without Alzheimer’s
When asked to describe a future without Alzheimer’s, Marino does not reach for science — though she would gladly discuss it. Instead, she turns to family.
“Alzheimer’s disease is not just the pathology of the individual with Alzheimer’s,” she said. “It’s the pathology of the individual and the family supporting them.”
She thinks about what it means to lose the ability to speak, eat, or recognize the people you love. She thinks about the caregivers — the estimated 13 million Americans who provided more than 19 billion hours of unpaid care in 2025 alone. She thinks about the infrastructure required to sustain it all.
“A future with no Alzheimer’s,” she added, “can really give, in the long term, a better life, in a broader sense.”
She points to the progress medicine has already made with other diseases that once seemed insurmountable, such as cancer or hypertension. These conditions, while serious, are now manageable in ways they were not a generation ago.
“I’m very optimistic,” she said. “We have better tools and understanding now. There is also emerging technology that really helps, and pipelines of clinical trials are testing approaches from many different angles. This allows us to get one step closer every day.”
The research question Marino has carried since 2011 is as clear today as it has ever been.
“Can we protect against Alzheimer’s disease?” she said. “That’s the big question. And that’s what I’m still trying to answer.”
SUPPORT BRAIN HEALTH AT UTMB
Dr. Marino’s work is one part of a larger story. At UTMB, researchers, clinicians, and educators across disciplines are working every day to understand, prevent, and treat brain diseases. The UTMB Brain Health Fund supports all of it — from early-stage discovery to patient care to the next generation of scientists who will carry this work forward.