Alzheimer’s disease gradually damages memory, thinking, and behavior and affects more than 7 million older adults in the United States. Researchers have long known that blood vessels in the brain deteriorate as Alzheimer’s progresses, particularly in people who carry APOE4. However, it has remained unclear why this vascular damage occurs and whether it directly contributes to neurodegeneration.

As a result, damage to cerebral circulation is often viewed as a consequence of Alzheimer’s disease rather than as an active process that may help drive the disease. The new Mount Sinai research offers evidence that APOE4 can directly alter brain blood vessels and interfere with the removal of harmful proteins.

How APOE4 Damages Brain Blood Vessels

In the study published in Cell on September 24, Mount Sinai scientists combined existing datasets to create a single-cell transcriptome atlas of blood vessels in the human brain. The atlas mapped gene activity across the different cells that form and support the brain’s vascular system, providing a detailed way to study how APOE4 affects blood vessel health.

The researchers found that APOE4 changes the behavior of pericytes. These cells normally help stabilize small blood vessels and support the blood-brain barrier. In the presence of APOE4, however, pericytes transformed into myofibroblast-like cells that produce scar tissue.

This transformation promoted vascular fibrosis and increased the accumulation of amyloid around blood vessels. These changes can impede blood flow and create conditions that promote neurodegeneration.

The researchers also found evidence that the process may be reversible. Blocking TGF-β signaling, which helps regulate cell-to-cell communication and tissue remodeling, restored pericyte coverage while reducing perivascular fibrosis and amyloid accumulation.

The findings were replicated over time in mice. Together, the results suggest that APOE4-associated vascular degeneration may be therapeutically reversible.

“Cerebrovascular damage 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 to preserve vascular function and limit amyloid accumulation.”

“We show that APOE4 converts vascular support cells into scar-forming cells, causing amyloid and abnormal protein deposits to accumulate around brain blood vessels,” said lead author Braxton R. Schulte, an MD/doctoral candidate in neuroscience and a research associate in the Blanchard Laboratory at the Icahn School of Medicine at Mount Sinai. “Through our experiments, we were able to block this protein accumulation process, revealing the potential for new treatments and strategies to protect cerebral circulation in people at high genetic risk for Alzheimer’s disease.”

Human miBrains Reveal Alzheimer’s and Parkinson’s Disease Mechanisms

Much of the research relied on miBrains, three-dimensional human brain tissue developed by the Mount Sinai team from induced pluripotent stem cells. The model reproduces important features of human brain tissue, including its vascular network.

The Blanchard laboratory combined results from miBrains with preclinical models, post-mortem human brain tissue, and transcriptome data. Each research system helped confirm and expand the observations made in the others.

By integrating these approaches, the scientists were able to reproduce events that occur before the severe vascular abnormalities observed in post-mortem human brain tissue. This allowed them to identify possible mechanisms behind the changes and rapidly test potential treatments.

APOE4 May Disrupt the Brain’s Protein-Clearance System

In the study published in Cell Stem Cell, researchers used miBrains to investigate another effect of APOE4: its role in the accumulation of abnormal proteins associated with neurodegenerative diseases.

The buildup of abnormal proteins is a hallmark of conditions such as Alzheimer’s disease and Parkinson’s disease. However, it is difficult to study exactly how these deposits form in the living human brain. The miBrain system gives researchers a way to observe related processes in complex human brain tissue under laboratory conditions.

miBrains contain major cell types found in the human brain, including neurons, supporting glial cells, myelin-producing cells, and the cells that form blood vessels. Similar to what occurs in the human brain, miBrains with APOE4 generated large amounts of abnormal alpha-synuclein, a protein strongly associated with Lewy body dementia and Parkinson’s disease.

Although alpha-synuclein has major clinical importance, scientists do not fully understand the cellular processes that cause it to accumulate.

Cholesterol Buildup Prevents Astrocytes From Removing Cellular Waste

The experiment revealed that APOE4 causes cholesterol to build up inside astrocytes, support cells that perform several important functions in maintaining brain health.

Excess cholesterol interfered with the astrocytes’ lysosomal waste-disposal system. As a result, the cells became less effective at breaking down alpha-synuclein. Instead of being removed, the protein accumulated and spread to neurons, where it formed harmful deposits.

These findings suggest that cholesterol metabolism in astrocytes, along with lysosomal function, may be an important therapeutic target for both Alzheimer’s and Parkinson’s diseases.

Using miBrains, researchers were able to track the sequence of events in complex human brain tissue. Their experiments linked APOE4 to lipid accumulation in astrocytes, reduced alpha-synuclein clearance, and the formation of toxic protein deposits.

The results indicate that both lipid metabolism and cellular waste-removal systems may offer potential treatment targets for neurodegenerative diseases.

miBrains Could Support Personalized Treatment Research

Another advantage of the miBrain system is that researchers can preserve tissue for future experiments.

“An important advance in our technology is the ability to cryopreserve miBrains with predefined cellular compositions and disease-associated factors,” said Dr. M., assistant professor of neuroscience and stem cell biology and regenerative medicine at the Icahn School of Medicine at Mount Sinai. “This capability increases the reproducibility and scalability of complex disease modeling and supports more efficient drug development and validation.”

Mount Sinai researchers are also developing miBrains derived from individual patients. This approach could eventually allow scientists to study why neurodegenerative diseases develop differently from person to person and how individual patients respond to potential treatments.

“At Mount Sinai, we create and cryopreserve miBrains from patients,” Dr. Blanchard added. “This enables personalized research into how neurodegenerative diseases develop and how individuals respond to treatment. By allowing potential treatments to be tested earlier and more efficiently, the miBrain platform could help bridge the gap between laboratory discovery and treatment for a wide range of diseases.”

Research Funding

The Cell study examining cerebral vascular degeneration was supported by the National Aeronautics and Space Administration (80ARC022CA004), the National Institutes of Health’s National Institute on Aging (R01AG089533, UH3NS115064, U54AG090669, T32GM146636), the SWT Foundation, and the CureAlz Fund.

The Cell Stem Cell study examining abnormal protein accumulation in the brain was supported by the National Aeronautics and Space Administration (80ARC022CA004), the Michael J. Fox Foundation for Parkinson’s Disease Research, the National Institute of Neurological Disorders and Stroke, and the Coordination of Science Across Parkinson’s Disease (ASAP-024297) through the National Institutes of Health’s National Institute on Aging (R01NS114239, UH3NS115064, 1U54AG090669-01, T32AG04968, F31NS13090), the CureAlz Fund, and the SWT Foundation.