UC Irvine Researchers Explore Vascular Dysfunction in Alzheimer’s Progression

The nonprofit organization Cure Alzheimer’s Fund (CureAlz), which supports research “with the highest probability of preventing, slowing or reversing Alzheimer’s disease,” recently awarded funding to a new multidisciplinary project led by two UC Irvine researchers.

Elizabeth Head, PhD, professor of pathology in the School of Medicine and co-director of the Center for Aging Research in Down Syndrome, and Vivek Swarup, PhD, professor of neurobiology and behavior in the Charlie Dunlop School of Biological Sciences, are teaming up to explore how changes in the brain’s blood vessels contribute to the onset and progression of dementia.

A Gap in Alzheimer’s Disease Research

“We came together through a shared recognition of a critical gap in Alzheimer’s disease research,” says Head, whose lab group is pioneering research in Down syndrome and Alzheimer’s disease. “Although cerebrovascular pathology is one of the most consistent features of both Down syndrome–associated Alzheimer’s disease (DSAD) and late-onset AD, its molecular mechanisms remain poorly defined.” Her long-standing neuropathological work in Down syndrome has revealed that vascular abnormalities — particularly cerebral amyloid angiopathy and blood–brain barrier breakdown — emerge early and progress predictably with age.

In parallel, Swarup’s lab group, focusing on spatial and single-cell multiomic studies, has uncovered profound endothelial and glial remodeling in Alzheimer’s disease. “By integrating these perspectives, we formulated the hypothesis that vascular dysfunction is not merely a downstream consequence of amyloid pathology in DSAD but an active, early driver of neurodegeneration that can be resolved only through spatially integrated transcriptomic and proteomic analyses,” says Swarup.

Through their CureAlz-funded project, they plan to test their hypothesis.

Building an Atlas of Vascular Pathology

Head will leverage her expertise to ensure rigorous phenotyping of cerebral amyloid angiopathy, blood–brain barrier disruption and regional vascular pathology. Swarup will apply cutting-edge spatial transcriptomic, single-nucleus RNA-seq and integrative network-biology approaches to map cell-type-specific transcriptional and proteomic programs within the neurovascular unit and to connect molecular signatures with precise anatomical and pathological context.

“The long-term goal,” says Swarup, “is to fundamentally reframe Alzheimer’s disease — particularly in Down syndrome — as a disorder in which cerebrovascular dysfunction plays a causal and potentially targetable role.”

Head further outlines the potential impact. “By generating the first integrated, single-cell, spatial multiomic atlas of vascular pathology in DSAD,” she says, “this work aims to identify molecular pathways that preserve or restore vascular integrity, inform safer and more effective therapeutic strategies, and yield biomarkers that can predict disease progression and treatment risk in both DSAD and the broader Alzheimer’s disease population.”

Data generated from this project will be shared with the Alzheimer’s disease and Down syndrome communities to accelerate future discoveries.

— Shani Murray