Healthcare (Commonwealth Union) – The well-being of the brain relies on more than its neurons alone. An intricate system of blood vessels and immune cells serves as its frontline defenders—regulating what passes through, clearing away debris, and shielding it from dangers through the formation of the blood-brain barrier.
According to new research from Gladstone Institutes and UC San Francisco (UCSF), numerous genetic risk factors for neurological conditions such as Alzheimer’s disease and stroke appear to influence these very protective cells.
“When studying diseases affecting the brain, most research has focused on its resident neurons,” explained Gladstone Investigator Andrew Yang, PhD, the senior author of the new findings. “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 study, published in Neuron, tackles a long-standing puzzle about the origins of genetic risk and points to weaknesses in the brain’s protective system as a possible trigger for neurological disorders.
For years, extensive genetic research has tied numerous DNA variants to an increased likelihood of conditions such as Alzheimer’s, Parkinson’s, and multiple sclerosis.
However, a major question has remained unresolved: more than 90 percent of these variations are not found within the protein-coding genes themselves, but in surrounding stretches of DNA once dismissed as “junk.” These regions act like intricate dimmer switches, regulating whether genes are switched on or off.
Until recently, scientists lacked a complete map linking these regulatory switches to the specific genes they control—and to the particular brain cells where they function. This gap has slowed progress from genetic findings to effective treatments.
The blood-brain barrier serves as the brain’s primary shield—a cellular checkpoint built from blood vessel cells, immune cells, and other supportive cell types that carefully regulate what enters the brain. Despite their importance, these cells have long been challenging to investigate, even with the most advanced genetic tools available.
To address this, researchers at Gladstone created a new method called MultiVINE-seq, which delicately extracts vascular and immune cells from postmortem human brain tissue.
For the first time, this technology enabled scientists to capture two key layers of information at once: patterns of gene activity and the regulatory “dimmer switch” controls—known as chromatin accessibility—within each individual cell. Using 30 brain samples from people both with and without neurological conditions, the team gained unprecedented insight into how genetic risk factors operate across all major types of brain cells.
In collaboration with Gladstone investigators Ryan Corces, PhD, and Katie Pollard, PhD, lead researchers Madigan Reid, PhD, and Shreya Menon combined their detailed single-cell atlas with large-scale genetic datasets focused on Alzheimer’s, stroke, and other neurological disorders. Their analysis pinpointed where disease-linked genetic variants were active—and surprisingly, many were most active in vascular and immune cells rather than neurons.
Reid pointed out that on prior occasions they knew these genetic variants were tied to higher disease risk, but they lacked clarity on where and how they functioned within brain barrier cell types. She further stated that their findings reveal that many of these variants are actually influencing blood vessel and immune cells inside the brain.
The study reveals that genetic risk factors impact on the brain’s barrier system in stroke and Alzheimer’s in different ways. Stroke-related variants lower the impact on the blood vessel structure, while Alzheimer’s variants enhance immune activity, particularly via a common PTK2B gene variant that drives overactive T cells near amyloid plaques. Since PTK2B is a target that can be treated by drugs, present cancer drugs could be repurposed for Alzheimer’s. The study highlights brain “guardian” cells at the brain–body interface as promising targets for therapies and lifestyle interventions, providing pathways for the protection of brain health without crossing the blood-brain barrier.
