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New evidence points to the brain's outer defenses
Recent research from Gladstone Institutes and UCSF reframes how we think about neurodegenerative disease risk. Instead of originating solely within neurons, genetic risk factors for conditions such as Alzheimer’s disease and stroke appear to act prominently in the specialized cells that form the brain's outer border: vascular cells and immune cells that compose the blood-brain barrier. This new perspective, published in Neuron, suggests that vulnerabilities in the brain’s protective interface can initiate or amplify disease processes.
Scientific background: the blood-brain barrier and regulatory DNA
The brain depends on more than neuronal networks to maintain function. Blood vessels, perivascular support cells, and immune cells collaborate to form the blood-brain barrier, a selective interface that controls nutrient passage, clears metabolic waste, and blocks pathogens and toxins. For decades, genome-wide association studies (GWAS) have linked many DNA variants to neurodegenerative and cerebrovascular disorders. Yet more than 90% of these variants lie outside protein-coding sequences, in regulatory regions historically called 'noncoding' or 'junk' DNA. These regions tune when and where genes are active — functioning more like dimmer switches than on/off lightbulbs — but until now researchers lacked a detailed map tying those switches to specific brain cell types and genes.
Methods: MultiVINE-seq and single-cell multi-omics
To overcome technical barriers to studying vascular and immune cells from human brain tissue, the Gladstone team developed MultiVINE-seq, a protocol that isolates vascular and immune cells gently from postmortem samples while preserving both gene expression and chromatin accessibility information. Chromatin accessibility reveals which upstream regulatory regions are open and likely to influence gene activity. By pairing transcriptomics with chromatin maps at single-cell resolution across 30 human brain samples, the investigators created a high-resolution atlas of cell-specific gene regulation at the blood-brain barrier.
Integrating genetic risk with cell-level data
Lead authors integrated the MultiVINE-seq atlas with large-scale GWAS data for Alzheimer’s, stroke, and other neurological disorders. This approach made it possible to localize the activity of disease-associated genetic variants to precise cell types. Strikingly, many variants previously assumed to act in neurons instead showed functional signatures in vascular and immune cells at the brain's borders.
Key discoveries: distinct mechanisms for stroke and Alzheimer’s
The study reveals that disease-associated variants do not all act the same way across barrier cells. Genetic drivers linked to stroke preferentially affect genes involved in the structural integrity of blood vessels. Those variants tend to map to chromatin regions controlling genes that maintain vessel stability and architecture, consistent with a model in which genetic risk increases the likelihood of vessel weakening and rupture.
By contrast, Alzheimer’s-associated variants were enriched in regulatory regions active in immune cells, particularly T cells, and in vascular immune signaling pathways. Rather than weakening vessel structure, the Alzheimer’s-linked variants appear to amplify immune activity at the blood-brain barrier, potentially promoting excessive inflammation and immune cell infiltration into brain tissue. This suggests fundamentally different upstream mechanisms: structural vulnerability for stroke versus dysregulated immune responses for Alzheimer’s.
PTK2B emerges as an immune amplifier linked to Alzheimer’s risk
Among Alzheimer’s-associated loci, a common variant near PTK2B stood out. Present in over a third of people, this variant shows strong regulatory activity in T cells and correlates with increased PTK2B expression. PTK2B is implicated in T cell activation and migration; enhanced expression could promote immune cell entry into the brain and elevate local inflammation. The authors observed PTK2B-high immune cells localized near amyloid plaques, the protein aggregates that mark Alzheimer’s pathology.
Crucially, PTK2B is considered a druggable target and inhibitors are being tested in oncology trials. The new findings raise the possibility of repurposing PTK2B-modulating drugs or designing new therapies that temper barrier immune activation as a strategy for Alzheimer’s prevention or treatment.
Implications for therapy, prevention, and research priorities
By highlighting vascular and immune cells at the brain’s interface, this study opens multiple translational opportunities. First, barrier cells are more accessible to systemic therapies than neurons behind the blood-brain barrier, potentially simplifying drug delivery. Second, because these cells are exposed to circulating factors, lifestyle and environmental exposures may interact with genetic risk at the barrier, suggesting novel prevention strategies that combine behavioral interventions with targeted therapeutics.
Finally, the multi-omics atlas and the MultiVINE-seq method create a valuable resource for the field, enabling researchers to map other disease-associated regulatory variants to specific cell types and signaling pathways. This cell-resolved approach should accelerate the identification of actionable targets and refine disease models that include non-neuronal drivers of neurodegeneration and cerebrovascular disease.
Expert Insight
Dr. Lena Hoffman, a fictional neuroimmunologist and science communicator, comments: 'This work is a paradigm shift. For too long we concentrated on neuron-centered models of neurodegeneration. Mapping regulatory DNA activity in vascular and immune cells demonstrates that the brain's interface with the body is an active player in disease risk. That has practical consequences: barrier cells are reachable by blood-borne drugs, and they respond to lifestyle exposures, so we have more levers to modify risk than previously appreciated.'
Dr. Hoffman adds: 'The finding that PTK2B variants heighten T cell signaling near amyloid deposits is particularly intriguing because it links common genetic variation, immune activation, and pathological features of Alzheimer’s. If follow-up studies confirm causality, drug repurposing studies could move relatively quickly into clinical evaluation.'
Next steps and future directions
Key next steps include validating causal relationships between specific regulatory variants, altered cell behavior at the blood-brain barrier, and clinical disease progression. Longitudinal human studies, experimental models that recapitulate barrier cell interactions, and clinical trials that test PTK2B inhibitors or other modulators of barrier immune activity will be required. Additionally, expanding MultiVINE-seq datasets to more diverse populations and disease stages will help determine how universal these mechanisms are across ages, ancestries, and environmental backgrounds.
Conclusion
This multi-omics study reframes genetic risk for Alzheimer’s and stroke by locating key functional effects in the cells that form the brain's external defenses. Rather than being secondary victims of neuronal decline, vascular and immune cells at the blood-brain barrier are implicated as primary sites where genetic variants act to raise disease risk. Differing mechanisms — structural weakening in stroke and heightened immune signaling in Alzheimer’s — point to tailored strategies for prevention and treatment. The study also introduces a new experimental toolkit and a cell-resolved atlas that will guide future research and therapeutic development, bringing barrier biology into the center of neurodegenerative disease science.
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