Alzheimer’s risk gene APOE4 may have a reversible weakness

MOUNT SINAI (NEW YORK, USA), 2 OCTOBER 2026 —

Researchers at Mount Sinai have uncovered new evidence showing that APOE4, the strongest known genetic risk factor for Alzheimer's disease, actively damages brain blood vessels and sabotages cellular waste systems, while also demonstrating that these destructive effects may be reversible.

The discoveries address a long-standing question in neurology regarding whether circulation damage in the brain is merely a consequence of Alzheimer's disease progression or a driver of it. By utilizing a new human brain tissue platform derived from stem cells alongside preclinical models, the research team mapped how the gene alters cell behavior and protein accumulation, offering pathways for potential treatments and earlier interventions.

In the Cell study published on September 24, scientists combined existing datasets to build a single-cell transcriptomic atlas of blood vessels in the human brain. This map detailed patterns of gene activity across cells that create and support the vascular system, revealing that APOE4 alters the behavior of pericytes. Normally, these cells help stabilize small blood vessels and support the blood-brain barrier.

In the presence of APOE4, however, pericytes transform into myofibroblast-like cells that produce scar tissue, promoting vascular fibrosis and increasing amyloid buildup around blood vessels.

The team found that blocking TGF-beta signaling, a pathway involved in cell communication and tissue remodeling, restored pericyte coverage and reduced both fibrosis and amyloid around blood vessels. Researchers successfully reproduced these results in aged APOE4 mice, demonstrating that vascular degeneration driven by the gene 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, according to corresponding author Joel W. Blanchard, who serves as Associate Professor of Neuroscience and Stem Cell Biology and Regenerative Medicine at the Icahn School of Medicine at Mount Sinai. Blanchard noted that the findings reveal new therapeutic targets for preserving vascular function and limiting amyloid accumulation.

First author Braxton R. Schuldt, an MD/PhD candidate in neuroscience and researcher in the Blanchard Laboratory, explained that the study shows APOE4 converts blood-vessel support cells into scar-producing cells, causing abnormal protein buildup around brain vessels. Through experiments, the team was able to block this protein buildup process, revealing possible new therapeutic treatment options and strategies to protect brain circulation in individuals at high genetic risk for Alzheimer's.

A major component of the research relied on miBrains, which are three-dimensional human brain tissue models developed by the Mount Sinai team from induced pluripotent stem cells. These models reproduce critical features of human brain tissue, including vascular networks and all major cell types such as neurons, supporting glial cells, and myelin-producing cells.

The Blanchard laboratory combined findings from miBrains with preclinical models, postmortem human brain tissue, and transcriptomic data to identify mechanisms behind vascular changes before severe abnormalities develop.

In the Cell Stem Cell study, researchers used miBrains to examine the role of APOE4 in the accumulation of abnormal proteins associated with neurodegenerative diseases like Alzheimer's and Parkinson's. Similar to human brain pathology, miBrains carrying APOE4 developed higher amounts of abnormal alpha-synuclein, the protein strongly associated with Lewy body dementia and Parkinson's disease.

The experiments revealed that APOE4 causes cholesterol to accumulate inside astrocytes, which are support cells responsible for maintaining brain health. This excess cholesterol interferes with the astrocytes' lysosomal waste-disposal systems, rendering the cells less effective at breaking down alpha-synuclein. Instead of being cleared away, the protein accumulates and spreads to neurons, contributing to harmful deposits.

The results suggest that cholesterol metabolism and cellular waste removal in astrocytes could serve as vital treatment targets for both Alzheimer's and Parkinson's diseases.

A key advantage of the miBrain system is the ability to preserve the tissue for future experiments.

Louise Mesentier-Louro, 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, stated that cryopreserving miBrains with predefined cellular compositions and disease-related factors improves the reproducibility and scalability of complex disease modeling while supporting more efficient drug development and validation.

Mount Sinai researchers are also developing patient-derived miBrains to investigate how neurodegenerative disease develops differently across individuals and how patients might respond to specific treatments. Blanchard noted that creating and cryopreserving miBrains from patients will enable personalized studies into disease development and therapeutic responses, helping bridge the gap between laboratory discoveries and treatments for a wide range of disorders.

The Cell study on vascular degeneration received financial support from 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, The SWT Foundation, and the CureAlz Fund.

The Cell Stem Cell study examining abnormal protein buildup was supported by the National Aeronautics and Space Administration under grant 80ARC022CA004, Aligning Science Across Parkinson's through grant ASAP-024297 via the Michael J. Fox Foundation for Parkinson's Research, and the National Institute of Neurological Disorders and Stroke and the National Institute on Aging at the National Institutes of Health under grants R01NS114239, UH3NS115064, 1U54AG090669-01, and T32AG04968.