Joel W. Blanchard, an associate professor of neuroscience at the Icahn School of Medicine at Mount Sinai, and his team report that the Alzheimer’s risk gene APOE4 drives a specific kind of scarring in the small blood vessels of the brain, and that blocking one signaling pathway undid it in aged mice and in lab-grown human brain tissue. The work was published in Cell on September 24, 2026.
Blanchard’s framing is blunt. “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,” he said in the Mount Sinai announcement.
Pericytes that turn into scar-makers
Pericytes are the cells that wrap and stabilize the brain’s smallest vessels. In the Cell paper, titled “A pericyte-to-myofibroblast transition links APOE4 to cerebrovascular degeneration,” the Mount Sinai group describes how APOE4 changes their behavior. According to the ScienceDaily account of the study, the pericytes turn into myofibroblast-like cells, the same type of cell that lays down scar tissue elsewhere in the body.
The Mount Sinai release, as carried by Newswise, connects that transition to vascular fibrosis and to a build-up of amyloid around the vessels, which could compromise blood flow and feed neurodegeneration. Braxton R. Schuldt, an MD/PhD candidate, is first author of the Cell paper.
The human-tissue side of the work matters because mouse vessels differ from human ones. News-Medical reports that the team assembled a single-cell transcriptomic atlas of human brain vasculature and analyzed postmortem human brain tissue, so that the findings in engineered tissue and in mice rest on more than animal biology alone. The three approaches are complementary, each covering a gap in the others: the stem-cell tissue is human but small and artificial, the mice are whole animals but not human, and the postmortem brains are real but frozen at a single moment.
TGF-beta blockade and the reversal
The reversal came from interrupting TGF-beta signaling, a pathway that pushes cells toward a scarring state. The News-Medical write-up says that in aged APOE4 mice, blocking it restored pericyte function and reduced both fibrosis and vascular amyloid. Neuroscience News adds that the amyloid fell to normal levels in those animals and that pericyte coverage of the vessels was restored.
The evidence comes from three systems. The team built “miBrains,” three-dimensional human brain tissue grown from induced pluripotent stem cells that contains neurons, glial cells and blood-vessel cells, and combined them with aged APOE4 mice and with postmortem human brain tissue. The reversal was demonstrated in the lab models and the mice. It was not tested in people, and no patient received a TGF-beta blocker in this work.
Mount Sinai also stresses what the miBrain platform adds for future work. Because the tissue is human-derived, reproducible and can be frozen, the team describes it as a way to test candidate drugs on models matched to an individual’s own cells, a step that mouse experiments cannot offer and that would precede any clinical trial by a long distance.
A second APOE4 problem inside astrocytes
A companion paper in Cell Stem Cell, led by first author Louise Mesentier-Louro, looked at a different cell type. It found that APOE4 causes cholesterol to build up inside astrocytes, the star-shaped support cells, and that this impairs the lysosomes that clear waste. One casualty is alpha-synuclein, the protein that clumps in Parkinson’s disease and Lewy body dementia, which the astrocytes then break down less well.
The two papers point at the same gene from opposite sides, one at the vessel wall and one at the waste-disposal machinery of the surrounding tissue. Mount Sinai says the lipid-handling and waste-removal pathways now count as candidate drug targets, and that miBrains could be used to test treatments on personalized models because the tissue can be cryopreserved.
APOE4 carrier prevalence
The gene is common. The Alzheimer’s Association estimates that 20 to 30 percent of people in the United States carry one or two copies of the APOE-e4 variant and that about 2 percent carry two. Researchers estimate that 40 to 65 percent of people diagnosed with Alzheimer’s have at least one copy. Inheriting it raises risk without guaranteeing the disease, and it can bring earlier symptom onset.
Those figures explain the interest in a reversible mechanism: a vascular process that is active rather than a late by-product would give drug developers a target before irreversible loss. The Mount Sinai group’s funders, listed in the announcement, are the National Institutes of Health, NASA, the Michael J. Fox Foundation, the CureAlz Fund and The SWT Foundation. Whether blocking TGF-beta can be done safely in the human brain, where the pathway has many other jobs, is not addressed by the animal data.
This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.
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