Mount Sinai researchers published two studies on September 24 detailing how APOE4—the strongest known genetic risk factor for Alzheimer’s disease—directly damages brain blood vessels and disrupts cellular waste disposal. The findings, appearing in Cell and Cell Stem Cell, demonstrate that these destructive vascular and metabolic changes are biologically active processes rather than mere late-stage consequences of neurodegeneration, and show they can be therapeutically reversed in preclinical models.
Mapping How APOE4 Transforms Brain Support Cells Into Scar Tissue
By integrating various existing datasets, researchers created a single-cell transcriptomic atlas of human brain blood vessels to reveal the precise ways in which vasculature deteriorates.
Researchers discovered that APOE4 alters the behavior of pericytes, which normally stabilize small blood vessels and maintain the blood-brain barrier. Instead of performing their standard support role, these cells transform into myofibroblast-like cells that produce scar tissue.
That cellular shift drives vascular fibrosis and accelerates amyloid buildup around brain vessels, ultimately restricting blood flow and encouraging neurodegeneration. However, experiments showed the damage is not permanent. Blocking TGF-β signaling restored pericyte coverage while reducing fibrosis and clearing amyloid in aged APOE4 mice.
“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,” said corresponding author Joel W. Blanchard, PhD, an Associate Professor of Stem Cell Biology and Regenerative Medicine, and Neuroscience, at the Icahn School of Medicine at Mount Sinai.
“We show that APOE4 converts blood-vessel support cells into scar-producing cells, causing amyloid or abnormal protein buildup to accumulate around the brain’s vessels,” said first author Braxton R. Schuldt, a researcher in the Blanchard Laboratory and MD/PhD candidate in Neuroscience at the Icahn School of Medicine at Mount Sinai.
Using miBrains to Uncover Cellular Waste Breakdown Failures
To investigate protein cleanup inside living human tissue, the research team relied on miBrains—three-dimensional human brain tissue models developed from induced pluripotent stem cells. These models reproduce complex human brain architecture, including functional blood vessels, neurons, supporting glial cells, and myelin-producing cells.
Using the miBrain platform for the Cell Stem Cell study, scientists tracked how APOE4 triggers the accumulation of alpha-synuclein, an abnormal protein strongly linked to Parkinson’s disease and Lewy body dementia. The experiments revealed that APOE4 causes cholesterol to build up inside astrocytes, the support cells responsible for maintaining brain health. That excess cholesterol jams the astrocytes’ lysosomal waste-disposal system, rendering them incapable of clearing alpha-synuclein before it spreads to neurons.
Research Insight: The miBrain platform can be cryopreserved with predefined cellular compositions, allowing laboratories to standardize complex disease modeling, improve experimental scalability, and test personalized treatments before clinical application.
Research Funding and Institutional Backing
The investigations received financial backing from several federal agencies and philanthropic organizations. The Cell vascular study was supported by the National Aeronautics and Space Administration under grant 80ARC022CA004, the National Institute on Aging at the National Institutes of Health through grants R01AG089533, UH3NS115064, U54AG090669, and T32GM146636, along with The SWT Foundation and the CureAlz Fund.
The Cell Stem Cell protein accumulation study drew support from the National Aeronautics and Space Administration (80ARC022CA004), Aligning Science Across Parkinson’s (ASAP-024297) via the Michael J. Fox Foundation for Parkinson’s Research, the National Institute on Aging and the National Institute of Neurological Disorders and Stroke via grants F31NS13090, T32AG04968, 1U54AG090669-01, UH3NS115064, and R01NS114239, as well as The SWT Foundation and the CureAlz Fund.
apoe4 genetic risk factor damages brain blood vessels and disrupts waste disposal
What is APOE4 and how does it relate to Alzheimer’s disease?
APOE4 is the strongest known genetic risk factor for developing Alzheimer’s disease. Research from Mount Sinai shows it actively damages brain blood vessels by turning support cells into scar-producing tissue and disrupts cellular waste disposal.
Can the vascular damage caused by APOE4 be reversed?
Yes. Preclinical experiments showed that blocking TGF-β signaling restored pericyte coverage, reduced fibrosis, and cleared amyloid buildup around blood vessels in aged APOE4 models.
What are miBrains?
miBrains are three-dimensional human brain tissue models developed from induced pluripotent stem cells. They feature complex networks of blood vessels, neurons, and glial cells, enabling researchers to study neurodegenerative disease mechanisms and test potential therapies.
How does APOE4 contribute to Parkinson’s-related proteins?
APOE4 causes cholesterol to accumulate inside astrocytes, which disrupts their lysosomal waste-removal systems and prevents them from breaking down alpha-synuclein, a protein linked to Parkinson’s disease and Lewy body dementia.
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