Mount Sinai researchers have found that the Alzheimer's risk gene APOE4 actively damages brain blood vessels by transforming support cells into scar-producing cells, and that blocking a single signaling pathway reversed those changes in experiments.
The Research
Scientists at the Icahn School of Medicine at Mount Sinai published two studies — one in Cell on September 24, 2026, and one in Cell Stem Cell — examining how APOE4, the strongest known genetic risk factor for Alzheimer's disease, affects the brain's vascular system. Alzheimer's affects more than 7 million older adults in the United States and progressively damages memory, thinking, and behavior.
The team, led by corresponding author Joel W. Blanchard, PhD, Associate Professor of Neuroscience and Stem Cell Biology, and first author Braxton R. Schuldt, an MD/PhD candidate, combined existing datasets to build a single-cell transcriptomic atlas of blood vessels in the human brain. This map showed patterns of gene activity across the different cells that build and support the brain's vascular system, allowing detailed examination of how APOE4 contributes to vascular degeneration.
They found that APOE4 altered the behavior of pericytes — cells that normally stabilize small blood vessels and support the blood-brain barrier. In the presence of APOE4, pericytes changed into myofibroblast-like cells that produce scar tissue. This transformation promoted vascular fibrosis and increased the buildup of amyloid around blood vessels, potentially interfering with blood flow and creating conditions that encourage neurodegeneration.
Crucially, the researchers found evidence this process could be reversed. Blocking TGF-β signaling — a pathway involved in cell communication and tissue remodeling — restored pericyte coverage while reducing fibrosis and amyloid around blood vessels. They reproduced the result in aged APOE4 mice, showing that vascular degeneration associated with APOE4 can be therapeutically reversed.
The research also relied on miBrains, three-dimensional human brain tissue developed from induced pluripotent stem cells that reproduces important features of human brain tissue, including its blood vessel network. The lab combined miBrains findings with preclinical models, postmortem human brain tissue, and transcriptomic data to confirm and expand on observations.
Why It Matters
Damage to the brain's blood vessels has often been treated as a late consequence of Alzheimer's rather than a driver of the disease. This research reframes vascular degeneration as a biologically active process caused by APOE4 that may be reversible. Because APOE4 is carried by roughly 14% of the population and increases Alzheimer's risk substantially, understanding this mechanism opens new therapeutic targets for Alzheimer's, Parkinson's, and other neurodegenerative diseases. It also suggests that maintaining vascular health may be more directly connected to cognitive resilience than previously appreciated.
"Damage to the brain's blood vessels is not simply a late consequence of Alzheimer's disease; it is a biologically active process caused by APOE4 that may be reversible," Blanchard said.
What You Can Do
According to the CDC and Alzheimer's Association, evidence-based habits that support brain vascular health include regular aerobic exercise, managing blood pressure and cholesterol, maintaining healthy blood sugar levels, eating a Mediterranean-style diet rich in vegetables and omega-3s, and getting consistent quality sleep. If you know you carry APOE4, discuss vascular risk factors with your physician.
Source: ScienceDaily Mind & Brain
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