APOE4, the strongest genetic risk factor for Alzheimer’s, linked to brain blood vessel damage that may be reversible

Researchers have identified how APOE4, considered the strongest genetic risk factor for Alzheimer’s disease, damages brain blood vessels and promotes the buildup of abnormal proteins. They said the process may be reversible.

According to Azer Life Science on the 24th (local time), researchers at the Icahn School of Medicine at Mount Sinai in the United States published findings on how APOE4 damages brain blood vessels in the journals Cell and Cell Stem Cell.

Alzheimer’s disease is a progressive brain disorder that affects more than 7 million older adults in the United States alone. Brain blood vessel damage has long been considered a consequence of Alzheimer’s disease, but the researchers found that APOE4 actively contributes to disease progression.

In the study published in Cell, the researchers built a single-cell transcriptomic map of human brain blood vessels and analyzed how APOE4 causes vascular degeneration. They found that APOE4 transformed pericytes, cells that stabilize small blood vessels and maintain the blood-brain barrier, into scar-forming myofibroblast-like cells.

This change promoted vascular fibrosis and increased amyloid buildup around blood vessels, creating conditions that could impair blood flow and cause neurodegeneration. The researchers said that blocking the TGF-β pathway, which is involved in signaling between cells, restored pericytes and reduced both fibrosis and vascular amyloid.

The same results were reproduced in aged APOE4 mice. Corresponding author Joel W. Blanchard, an associate professor of neuroscience at the Icahn School of Medicine, said, “Brain blood vessel damage is not simply a late-stage consequence; it is a biologically active process caused by APOE4, and it is reversible.”

In the Cell Stem Cell study, the researchers used a 3D human brain tissue model they developed, called miBrains, to investigate how APOE4 promotes abnormal protein buildup. Derived from induced pluripotent stem cells, miBrains contain all the major cell types of the human brain.

Experiments showed that APOE4 caused cholesterol to accumulate in astrocytes, which are important for maintaining brain health. Excess cholesterol impaired the astrocytes’ lysosomal waste-processing function, reducing their ability to break down alpha-synuclein. The protein then aggregated and spread to neurons, forming harmful deposits.

Alpha-synuclein is a protein primarily associated with Lewy body dementia and Parkinson’s disease. The researchers said astrocyte cholesterol metabolism and lysosomal function could be promising therapeutic targets for Alzheimer’s and Parkinson’s diseases.

One advantage of miBrains is that they can be cryopreserved with their cellular composition and disease-related factors predetermined. First author Louise Mezhantieru, an assistant professor of neuroscience at the Icahn School of Medicine, said, “The key advance of this technology is that it improves reproducibility and scalability, supporting more efficient drug development and validation.”

Associate Professor Blanchard added, “At Mount Sinai, we are creating and cryopreserving patient-derived miBrains,” adding that “this will make personalized research possible into how neurodegenerative diseases develop and how individuals may respond to treatment.”