Alzheimer’s disease remains one of the most pressing neurological challenges of our time, affecting millions worldwide and unfolding through a complex interplay of amyloid buildup, tau pathology, inflammation, and vascular injury. While much progress has been made in understanding these processes, an important piece of the puzzle—how changes in the brain’s blood vessels contribute to the onset and progression of dementia—remains underexplored. A particularly informative window into this biology comes from people with Down syndrome, who carry a third copy of chromosome 21. Because chromosome 21 includes several genes involved in amyloid production and inflammatory signaling, nearly all adults with Down syndrome develop Alzheimer’s pathology by their early forties. This makes Down syndrome–associated Alzheimer’s disease (DSAD) a uniquely powerful cohort for identifying the earliest molecular events that drive vascular damage and accelerate neurodegeneration.
In DSAD, amyloid accumulates not only in brain tissue but also within the walls of blood vessels, leading to severe cerebral amyloid angiopathy (CAA). Even though adults with Down syndrome typically have fewer traditional vascular risk factors, they experience significant cerebrovascular changes, white matter injury, microbleeds, and blood–brain barrier breakdown, all of which can worsen cognitive decline. Recent national cohort studies have shown that these vascular and inflammatory changes begin decades before symptoms, underscoring how early and vascular dysfunction may be in DSAD. Yet, the vascular biology of DSAD has received far less mechanistic study than in late-onset Alzheimer’s disease, leaving critical questions unanswered. Filling this gap is essential not only for understanding disease progression, but also for improving safety and therapeutic responsiveness as individuals with Down syndrome begin participating in Alzheimer’s clinical trials.
To address this need, Dr. Head and Dr. Swarup propose an integrated, spatial multi-omic study to examine the cerebrovascular system at an unprecedented level of detail. They will combine spatial transcriptomics, spatial proteomics, and laser-capture microdissection in brain tissue from individuals with DSAD, late-onset AD, and neurotypical controls. The combined approach preserves the architecture of blood vessels and surrounding cells, allowing the team to map how endothelial cells, pericytes, astrocytes, and microglia change across the full spectrum of CAA severity. Preliminary data from their labs show clear changes in vascular cell states and protein expression in DSAD, demonstrating both the feasibility and the promise of this integrated strategy.
They hypothesize that vascular dysfunction is a critical pathway driving Alzheimer’s progression in DSAD, shaped by lifelong amyloid overproduction and the triplication of chromosome 21 genes.
They will investigate this hypothesis using two aims. The first will define how vascular and perivascular cells change at the RNA level in regions with and without CAA. The second will determine how these transcriptional programs translate into protein remodeling within the same microdissected vessels. Together, these aims will create the first spatially resolved, multi-omic atlas of cerebrovascular pathology in DSAD.
The impact of this work is far-reaching. By establishing how vascular injury emerges and evolves in DSAD, this study will reveal new therapeutic targets, clarify risks associated with anti-amyloid treatments, and identify protein biomarkers that may one day aid early detection. Through their complementary expertise in Down syndrome neuropathology and cutting-edge multi-omics, Drs. Head and Swarup will generate a foundational resource for the field, one that could reshape our understanding of vascular contributions to Alzheimer’s disease in both genetic and sporadic forms.
