The same cells that guard the brain may play a key role in stroke and Alzheimer's disease

The health of the brain depends on more than just its neurons. A complex network of blood vessels and immune cells act as the brain’s devoted guardians – they control what gets in, clear out waste, and protect it from threats by forming the blood-brain barrier.

A new study by researchers at the Gladstone Institutes and the University of California, San Francisco (UCSF) shows that many genetic risk factors for neurological diseases such as Alzheimer's and stroke act in these protective cells.

“When studying diseases that affect the brain, most research has focused on the neurons in the brain,” said Andrew C. Yang, PhD, a Gladstone Institutes researcher and senior author of the new study. “I hope our findings will spark greater interest in the cells that form the boundaries of the brain, since they may play a key role in diseases like Alzheimer’s.”

The findings, published in the journal Neuron, address a long-standing question about where genetic risk begins, and suggest that a vulnerability in the brain's defence system may be a key trigger for the disease.

Mapping the Brain's Defenders

Over the years, large-scale genetic studies have linked dozens of DNA variants to an increased risk of neurological diseases such as Alzheimer's, Parkinson's, or multiple sclerosis.

But a major mystery remained: More than 90 percent of these variants are located not in the genes themselves, but in surrounding regions of DNA that do not code for proteins, previously mistakenly called “junk DNA.” These regions act as complex regulators that turn genes on or off.

Until now, scientists have lacked a complete map of exactly which regulators control which genes and in which brain cells they act, which has prevented them from moving from genetic discoveries to new treatments.

New technology provides answers

The blood-brain barrier is the brain's first line of defense. It is a cellular boundary formed by blood vessel cells, immune cells, and other support cells that carefully control access to the brain.

But these important cells have been difficult to study, even with the most powerful genetic techniques. To overcome this, Gladstone’s team developed a technology called MultiVINE-seq that allows them to gently isolate vascular and immune cells from postmortem human brain tissue.

The technology allowed for the first time to simultaneously map two layers of information: gene activity and chromatin access patterns (regulator settings) in each cell. The scientists studied 30 brain samples from people with and without neurological diseases, giving them a detailed look at how genetic risk variants act in different types of brain cells.

Along with researchers Ryan Corses and Katie Pollard, lead authors Madigan Reid and Shreya Menon combined their single-cell atlas with large-scale genetic data on Alzheimer’s, stroke, and other brain diseases. This allowed them to pinpoint where disease-associated variants are active — and many were found to be active in vascular and immune cells, not neurons.

“We knew before that these genetic variants increased the risk of disease, but we didn’t know where or how they acted in the context of brain barrier cells,” Reid says. “Our study shows that many of them function specifically in the blood vessels and immune cells of the brain.”

Different diseases - different disorders

One of the most striking findings of the study is that genetic risk factors affect the brain barrier system in fundamentally different ways depending on the disease.

“We were surprised to see that the genetic drivers of stroke and Alzheimer’s disease had such different effects, even though both diseases affect the blood vessels of the brain,” Reid says. “This suggests that the mechanisms are indeed different: structural weakening of the vessels in stroke and impaired immune signaling in Alzheimer’s.”

In stroke, genetic variants primarily affect genes that control the structural integrity of blood vessels, potentially weakening them. While in Alzheimer's, they boost genes that regulate immune activity, suggesting that increased inflammation, rather than weak blood vessels, is the key factor.

Among the variants associated with Alzheimer’s, one stood out — a common variant near the PTK2B gene, which is present in more than a third of the population. It was most active in T cells, a type of immune cell. The variant boosts gene expression, which can stimulate T cells to activate and enter the brain, leading to hyperactivation of the immune system. The team found these “overloaded” T cells near amyloid plaques, the protein clumps that are characteristic of Alzheimer’s.

“Scientists are still debating the role of T cells and other components of the immune system in Alzheimer’s disease,” says Young. “Here we present genetic evidence in humans that a common risk factor for Alzheimer’s may act through T cells.”

Interestingly, PTK2B is already a known drug target, and drugs that inhibit its activity are already in clinical trials for cancer. The new study opens the possibility of exploring whether such drugs could be repurposed for Alzheimer’s disease.

The Importance of Location

The results of a study of the brain's "defender cells" open up two new possibilities for protecting it.

Because these cells sit at a critical juncture between the brain and body, they are constantly exposed to lifestyle and environmental factors that can interact with genetic predisposition to promote disease. Their location also makes them a promising target for therapy, as it potentially allows drugs to boost the brain’s defenses from the outside without having to pass through the complex blood-brain barrier.

“This work brings vascular and immune cells in the brain to the forefront,” says Young. “Given their unique position and role in connecting the brain to the body and the outside world, our work may lead to new, more accessible drug targets and prevention strategies that protect the brain from the outside in.”