Study Links Blood Vessels and Immune Cells to Alzheimer's and Stroke

The brain's health depends on more than just its neurons. A complex network of blood vessels and immune cells acts as the brain's dedicated guardians—controlling what enters, cleaning up waste, and protecting it from threats by forming the blood-brain barrier.

A new study from Gladstone Institutes and UC San Francisco (UCSF) reveals that many genetic risk factors for neurological diseases like Alzheimer's and stroke exert their effects within these very guardian cells.

When studying diseases affecting the brain, most research has focused on its resident neurons. Gladstone Investigator Andrew C. Yang, PhD, senior author of the new study, says, \"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 findings, published in Neuron, address a long-standing question about where genetic risk begins and suggest that vulnerabilities in the brain's defense system may be a key trigger for disease.

Mapping the Brain's Guardians

For years, large-scale genetic studies have linked dozens of DNA variants to a higher risk of neurological diseases like Alzheimer's, Parkinson's, or multiple sclerosis. Yet, a major mystery has persisted: over 90% of these variants lie not in the genes themselves, but in the surrounding DNA that does not contain the code for making proteins, once dismissed as \"junk DNA.\" These regions act as complex dimmer switches, turning genes on or off.

A New Technology Finds Answers

The blood-brain barrier is the brain's frontline defense—a cellular border made up of blood vessel cells, immune cells, and other supporting cells that meticulously controls access to the brain. To overcome the challenge of studying these important cells, the Gladstone team developed MultiVINE-seq, a technology that gently isolates the vascular and immune cells from postmortem human brain tissue.

This technology allowed the team, for the first time, to simultaneously map gene activity and the \"dimmer switch\" settings—known as chromatin accessibility—within each cell. The scientists studied 30 brain samples from individuals with and without neurological disease, giving them a detailed look at how genetic risk variants function across all major brain cell types.

Different Diseases, Different Disruptions

One of the study's most striking findings is that genetic risk variants affect the brain's barrier system in fundamentally different ways, depending on the disease. In stroke, genetic variants primarily affected genes responsible for the structural integrity of blood vessels, potentially weakening the vessels' physical structure. Whereas in Alzheimer's, the variants amplified genes that regulate immune activity, suggesting that overactive inflammation—not structural weakness—is the key issue.

Among the Alzheimer's-associated variants, one stood out. A common variant near the PTK2B gene, which is found in more than a third of the population, was most active in T cells, a type of immune cell. The variant enhances expression of the gene, which may promote T cell activation and entry into the brain, putting immune cells into overdrive.

Excitingly, PTK2B is a known \"druggable\" target, and therapies that inhibit its function are already in clinical trials for cancer. The new study opens a fresh avenue to investigate whether such drugs could be repurposed for Alzheimer's disease.

Location, Location, Location

The study's findings on the brain's \"guardian\" cells point to two new opportunities for protecting the brain. The cells are continually influenced by lifestyle and environmental exposures, which could synergize with genetic predispositions to drive disease. Their location also makes them a promising target for future therapies, potentially allowing for drugs that can bolster the brain's defenses from the \"outside\" without needing to cross the formidable blood-brain barrier.

About the Study

The study, \"Human brain vascular multi-omics elucidates disease risk associations,\" was published in the journal Neuron on July 28, 2025.

In addition to Yang, Reid, Corces, and Pollard, the study's other authors are Shreya Menon, Hao Liu, Haoyue Zhou, Zhirui Hu, Bella Ding, Zimo Zhang, Sophia Nelson, and Amanda Apolonio of Gladstone; Simon Frerich of UC San Francisco; Shahram Oveisgharan and David A. Bennett of Rush University Medical Center; and Martin Dichgans of LMU Munich.

The work was supported by various organizations including the National Institute of Neurological Disorders and Stroke, Alzheimer's Association, and National Institute of Aging.

About Gladstone Institutes

Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. Established in 1979, it is located in the Mission Bay neighborhood of San Francisco.