Mount Sinai researchers have uncovered new details about how APOE4, the strongest known genetic risk factor for Alzheimer's disease, may contribute to brain damage. Two studies published in Cell and Cell Stem Cell show that the gene can damage blood vessels in the brain and encourage the accumulation of abnormal proteins associated with neurodegenerative disease. The findings point to disease processes that may be reversible and also highlight a new human brain tissue platform derived from stem cells that could speed up the search for treatments.
Alzheimer's disease gradually damages memory, thinking, and behavior and affects more than 7 million older adults in the United States. Researchers have known for years that blood vessels in the brain deteriorate as Alzheimer's progresses, especially in people who carry APOE4. What has been less clear is why this happens and whether the vascular damage contributes directly to the disease.
Because of that uncertainty, damage to the brain's circulation has often been treated as a consequence of Alzheimer's rather than as a process that could help drive it. Mapping How APOE4 Damages Brain Blood Vessels For the Cell study published on September 24, Mount Sinai scientists combined existing datasets to build a single cell transcriptomic atlas of blood vessels in the human brain. The resulting map showed patterns of gene activity across the different cells that create and support the brain's vascular system, giving researchers a detailed way to examine how APOE4 contributes to vascular degeneration.
The team found that APOE4 altered the behavior of pericytes. These cells normally help stabilize small blood vessels and support the blood brain barrier. In the presence of APOE4, however, the pericytes changed into myofibroblast-like cells that produce scar tissue.
That transformation promoted vascular fibrosis and increased the buildup of amyloid around blood vessels. These changes could interfere with blood flow and create conditions that encourage neurodegeneration. The researchers also found evidence that this process could be reversed.
Blocking TGF-β signaling, which plays a role in communication between cells and in tissue remodeling, restored pericyte coverage while reducing fibrosis and amyloid around blood vessels. The researchers reproduced the result in aged APOE4 mice, showing that the vascular degeneration associated with APOE4 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.
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