How the APOE4 gene damages brain blood vessels in Alzheimer's disease
· Medical Xpressedited by Sadie Harley, reviewed by Robert Egan
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Mount Sinai researchers have identified how APOE4, the strongest genetic risk factor for Alzheimer's disease, damages the brain's blood vessels and promotes the buildup of abnormal proteins linked to neurodegenerative disease. Published in Cell and Cell Stem Cell, the studies identify potentially reversible disease mechanisms and demonstrate how a new stem cell-derived human brain tissue platform can accelerate mechanistic discovery and therapeutic development.
Alzheimer's disease is a progressive brain disorder that gradually impairs memory, thinking and behavior. It affects more than 7 million older adults in the United States. Scientists have long known that the brain's blood vessels deteriorate during the disease, particularly in people with APOE4, but the underlying mechanisms have remained unclear.
As a result, cerebrovascular damage has often been viewed as a downstream consequence of Alzheimer's disease rather than a process that actively contributes to disease progression.
APOE4 turns vessel support cells into scar-forming cells
In the Cell study, Mount Sinai researchers combined existing datasets to create a single-cell transcriptomic atlas of the human brain's vasculature. This detailed map of gene activity across cells that form and support blood vessels allowed the team to investigate how APOE4 promotes cerebrovascular degeneration.
They found that APOE4 caused pericytes, cells that normally stabilize small blood vessels and help maintain the blood-brain barrier, to transform into scar-forming myofibroblast-like cells. This transition promoted vascular fibrosis and increased amyloid accumulation around the vessels, creating conditions that may compromise blood flow and promote neurodegeneration.
Importantly, blocking TGF-β signaling, a pathway involved in cellular communication and tissue remodeling, restored pericyte coverage and reduced both fibrosis and vascular amyloid. The team reproduced this finding in aged APOE4 mice, showing that APOE4-associated cerebrovascular degeneration can be therapeutically reversed.
"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, Ph.D., associate professor of neuroscience and stem cell biology and regenerative medicine at the Icahn School of Medicine at Mount Sinai.
"These findings reveal new therapeutic targets for preserving vascular function and limiting amyloid accumulation."
"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. Through our experiments, we were able to block this protein buildup process, revealing possible new therapeutic treatment options and strategies for protecting the brain's circulation in people at high genetic risk for Alzheimer's disease," said first author Braxton R. Schuldt, M.D./Ph.D. candidate in neuroscience and researcher in the Blanchard Laboratory at the Icahn School of Medicine at Mount Sinai.
Human brain tissue models trace vascular damage
The study used miBrains, three-dimensional human brain tissue developed by the Mount Sinai team and derived from induced pluripotent stem cells, to model key features of human brain tissue and its vascular network. The Blanchard lab integrated preclinical models, postmortem human brain tissue, transcriptomic data and miBrains. Each system validated and extended findings from the others.
This approach enabled the team to recreate the events leading up to the end-stage vascular pathologies observed in postmortem human brain tissue, define the underlying mechanisms and rapidly test potential therapeutics.
Cholesterol buildup disrupts protein clearance
In the Cell Stem Cell study, the Blanchard lab used miBrains to investigate how APOE4 promotes the buildup of abnormal proteins in neurodegenerative disease. Such protein accumulation is a hallmark of disorders including Alzheimer's and Parkinson's disease, but studying how it develops in the living human brain is exceptionally difficult. The miBrain provides a window into these otherwise inaccessible processes in complex, human brain-like tissue.
miBrains contain all the major cell types found in the human brain, including neurons, supporting glial cells, myelin-producing cells and cells that form blood vessels. Like the human brain, miBrains carrying APOE4 accumulate higher levels of abnormal alpha-synuclein, a protein most commonly associated with Lewy body dementia and Parkinson's disease.
Despite its broad clinical significance, the cellular mechanisms that cause alpha-synuclein to accumulate have been poorly understood.
Experiments showed that APOE4 causes cholesterol to accumulate in astrocytes, supporting cells with essential roles in maintaining brain health. This excess cholesterol impairs the astrocytes' lysosomal waste-disposal system, reducing their ability to break down alpha-synuclein. The protein instead aggregates and spreads to neurons, leading to harmful protein deposits.
The findings identify cholesterol metabolism in astrocytes and lysosomal function as promising therapeutic targets for Alzheimer's and Parkinson's disease.
The miBrain model allowed researchers to study, in complex human brain-like tissue, how genetic risk factors such as APOE4 promote the buildup of harmful proteins associated with neurodegenerative disease. The researchers identified a chain of events linking APOE4 to lipid accumulation in astrocytes, impaired clearance of alpha-synuclein and toxic protein deposits, pointing to lipid metabolism and cellular waste-removal pathways as potential therapeutic targets.
Cryopreserved miBrains support personalized testing
"A key advance of our technology is that miBrains with predefined cellular compositions and disease-related factors can be cryopreserved," said Louise Mesentier-Louro, Ph.D., assistant professor of neuroscience and stem cell biology and regenerative medicine at the Icahn School of Medicine at Mount Sinai and first author of the Cell Stem Cell study.
"This capability improves reproducibility and scalability of complex disease modeling and supports more efficient drug development and validation."
"At Mount Sinai, we are creating and cryopreserving miBrains from patients," Blanchard added. "This will enable personalized studies into how neurodegenerative disease develops and how individuals may respond to therapies.
"By enabling potential therapies to be tested earlier and more efficiently, the miBrain platform could help bridge the gap between laboratory discoveries and treatments for a broad range of disorders."
Publication details
A pericyte-to-myofibroblast transition links APOE4 to cerebrovascular degeneration, Cell (2026). DOI: 10.1016/j.cell.2026.08.058. www.cell.com/cell/fulltext/S0092-8674(26)01069-X
Louise A. Mesentier-Louro et al, Cholesterol dysregulation in APOE4 astrocytes promotes α-synuclein pathology in miBrains, Cell Stem Cell (2026). DOI: 10.1016/j.stem.2026.08.001
Journal information: Cell Stem Cell , Cell
Key medical concepts
Apolipoprotein E4Pericytesalpha-SynucleinCholesterol
Clinical categories
NeurologyClinical genetics Provided by The Mount Sinai Hospital Who's behind this story?
Sadie Harley
BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →
Robert Egan
Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →
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