A groundbreaking study reveals that genetic risks for devastating neurological diseases might not originate in our neurons, but in the very cells that form the brain’s last line of defense.
For decades, the story of brain disease has been a story about neurons. These intricate, electrically-charged cells, the brain’s primary residents, have been the central characters in our quest to understand conditions like Alzheimer’s, Parkinson’s, and stroke. But what if we’ve been focusing on the wrong part of the story? A paradigm-shifting study from researchers at Gladstone Institutes and UC San Francisco (UCSF) suggests we might need to turn our attention from the brain’s interior to its heavily fortified border. The findings propose that the seeds of disease may be sown not in the neurons themselves, but in the complex network of guardian cells that form the blood-brain barrier.
This protective wall is far more than a simple fence. It’s a dynamic, living interface composed of blood vessel cells, specialized immune cells, and other support structures. Together, they act as the brain’s meticulous gatekeepers, controlling what gets in, diligently cleaning up waste, and mounting a defense against any potential threats. According to Dr. Andrew C. Yang, a Gladstone Investigator and the senior author of the new study, this border has been underappreciated. “When studying diseases affecting the brain, most research has focused on its resident neurons,” he explains. “I hope our findings lead to more interest in the cells forming the brain’s borders, which might actually take center stage in diseases like Alzheimer’s.”
The Mystery of the Genetic Switches
The journey to this discovery began with a long-standing genetic puzzle. For years, massive genome-wide association studies (GWAS) have successfully linked dozens of specific DNA variants to a higher risk of developing neurological diseases. The frustrating part? Over 90% of these risk-associated variants don’t lie within the genes that code for proteins. Instead, they are found in the vast, non-coding regions of our DNA, once dismissively labeled “junk DNA.”
We now know these regions are anything but junk. They function as a vast and complex control panel of “dimmer switches,” technically known as regulatory elements, that turn the activity of genes up or down. The problem was, scientists lacked a complete map. They didn’t know which switches controlled which genes, or, crucially, in which specific cell types within the brain they were active. This knowledge gap has been a major roadblock, preventing the translation of genetic discoveries into effective treatments. How can you fix a faulty switch if you don’t know what it controls or where it’s located?
A New Lens on the Brain’s Guardians
To solve this, the research team had to overcome a significant technical hurdle. The cells making up the blood-brain barrier are notoriously difficult to isolate and study with precision. The team, led by Dr. Yang, developed a novel technology called MultiVINE-seq. This technique allows for the gentle extraction of these delicate vascular and immune cells from postmortem human brain tissue.
More importantly, MultiVINE-seq enabled the scientists to simultaneously map two critical layers of information within each individual cell: its gene activity (which genes are “on”) and its chromatin accessibility (which “dimmer switches” are available to be flipped). By analyzing 30 brain samples from individuals with and without neurological diseases, they created an unprecedentedly detailed atlas of how the brain’s border cells function.
By integrating this new atlas with the massive datasets from previous genetic studies, the team could finally see where the disease-associated genetic variants were doing their work. The results were striking. A significant number of these variants were not active in neurons, as long assumed, but were instead flipping switches within the vascular and immune cells of the brain’s border. “Before this, we knew these genetic variants increased disease risk, but we didn’t know where or how they acted in the context of brain barrier cell types,” says Dr. Madigan Reid, a lead author of the study. “Our study shows that many of the variants are actually functioning in blood vessels and immune cells in the brain.”
Different Diseases, Distinct Disruptions
One of the most compelling findings was that genetic risks disrupt the brain’s barrier system in fundamentally different ways depending on the disease. It’s not a one-size-fits-all failure.
For stroke, the genetic variants primarily impacted genes responsible for the physical structure and integrity of the blood vessels. This suggests that in stroke, the risk comes from a potential weakening of the brain’s plumbing, making it more susceptible to rupture or blockage.
In Alzheimer’s disease, however, the story was completely different. The risk variants didn’t seem to affect structural genes. Instead, they amplified genes that regulate immune activity. This points to a dysfunctional immune response and overactive inflammation as a key driver of the disease, rather than a simple structural weakness. “We were surprised to see that the genetic drivers for stroke and Alzheimer’s had such distinct effects,” Reid notes. “That tells us they involve really distinct mechanisms: structural weakening in stroke, and dysfunctional immune signaling in Alzheimer’s.”
A Druggable Target for Alzheimer’s
Digging deeper into the Alzheimer’s data, one variant stood out. A common variant located near a gene called PTK2B, present in over a third of the population, was found to be most active in T cells, a specific type of immune cell. The variant acts to enhance the expression of the PTK2B gene, which appears to put these T cells into overdrive, promoting their activation and potential entry into the brain. The team even found these super-charged immune cells clustered near the infamous amyloid plaques, the sticky protein aggregates that are a hallmark of Alzheimer’s disease.
This provides powerful human genetic evidence supporting the increasingly debated role of the peripheral immune system in Alzheimer’s. “Here, we provide genetic evidence in humans that a common Alzheimer’s risk factor may work through T cells,” Yang states.
Excitingly, this discovery opens a direct path toward a potential new therapy. PTK2B is a known “druggable” target. In fact, drugs that inhibit its function are already undergoing clinical trials for cancer treatment. This new research provides a strong rationale for investigating whether these same drugs could be repurposed to calm the overactive immune response at the brain’s border and offer a new way to fight Alzheimer’s.
A New Frontier: Protecting the Brain from the Outside In
This research fundamentally reframes our understanding of brain health. By placing the brain’s vascular and immune cells in the spotlight, it opens up two promising new avenues for intervention.
First, because these cells sit at the critical interface between the brain and the rest of the body, they are constantly influenced by our lifestyle and environment. This suggests that genetic predispositions might interact with factors like diet, exercise, and exposure to inflammation to either protect or endanger the brain.
Second, their location makes them a far more accessible target for future therapies. Developing drugs that can cross the formidable blood-brain barrier is a monumental challenge in neurology. But if the problem starts at the barrier itself, it may be possible to develop treatments that can bolster the brain’s defenses from the “outside,” without ever needing to get in.
“This work brings the brain’s vascular and immune cells into the spotlight,” Yang concludes. “Given their unique location and role in establishing the brain’s relationship with the body and outside world, our work could inform new, more accessible drug targets and lifestyle interventions to protect the brain from the outside in.”
Reference
Yang, A. C., Reid, M., Corces, R., Pollard, K., Menon, S., Liu, H., Zhou, H., Hu, Z., Ding, B., Zhang, Z., Nelson, S., Apolonio, A., Frerich, S., Oveisgharan, S., Bennett, D. A., & Dichgans, M. (2025). Human brain vascular multi-omics elucidates disease risk associations. Neuron. Published online July 28, 2025.
