Alzheimer’s risk gene APOE4 may have a reversible weakness

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.

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. Blanchard, PhD, 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 for preserving vascular function and limiting amyloid accumulation."

"We show that APOE4 converts blood-vessel support cells into scar-producing cells, causing amyloid or abnormal protein buildup to accumulate around the brain's vessels. Through our experiments, we were able to block this protein buildup process, revealing possible new therapeutic treatment options and strategies for protecting the brain's circulation in people at high genetic risk for Alzheimer's disease," said first author Braxton R. Schuldt, MD/PhD candidate in Neuroscience and researcher in the Blanchard Laboratory at the Icahn School of Medicine at Mount Sinai.

A major part 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 network of blood vessels.

The Blanchard laboratory combined findings from miBrains with preclinical models, postmortem human brain tissue, and transcriptomic data. Each approach helped confirm and expand on observations made with the others.

By bringing these systems together, the scientists were able to recreate events that occur before the severe vascular abnormalities seen in postmortem human brain tissue. They could then identify the mechanisms behind those changes and quickly test possible treatments.

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