Alzheimer’s risk gene APOE4 may have a reversible weakness

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. 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.

Human miBrains Reveal Disease Mechanisms

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.

APOE4 May Also Disrupt the Brain's Protein Cleanup

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.

Abnormal protein buildup is a defining feature of conditions such as Alzheimer's and Parkinson's disease. However, investigating exactly how these deposits form inside a living human brain is extremely difficult. The miBrain system gives scientists a way to observe related processes in complex human brain-like tissue under laboratory conditions.

miBrains include all of the major cell types present in the human brain, including neurons, supporting glial cells, myelin producing cells, and cells that make up blood vessels. Similar to what happens in the human brain, miBrains carrying APOE4 developed higher amounts of abnormal alpha-synuclein. This protein is most strongly associated with Lewy body dementia and Parkinson's disease.

Although alpha-synuclein has major clinical importance, researchers have not fully understood the cellular processes that cause it to accumulate.

Cholesterol Buildup Disrupts Cellular Waste Removal

The experiments revealed that APOE4 causes cholesterol to accumulate inside astrocytes, support cells that perform several essential functions in maintaining brain health.

That 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 cleared away, the protein accumulated and spread to neurons, where it contributed to harmful deposits.

These findings suggest that cholesterol metabolism inside astrocytes, along with lysosomal function, could become important treatment targets for both Alzheimer's and Parkinson's disease.

Using miBrains, the researchers were able to follow the chain of events in complex human brain-like tissue. Their experiments connected APOE4 with lipid buildup in astrocytes, weaker clearance of alpha-synuclein, and the formation of toxic protein deposits.

The results point to both lipid metabolism and cellular waste removal systems as potential therapeutic targets in neurodegenerative disease.

A Platform for Testing Personalized Treatments

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

"A key advance of our technology is that miBrains with predefined cellular compositions and disease-related factors can be cryopreserved," said Louise Mesentier-Louro, PhD, 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. "This capability improves 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, which could eventually allow scientists to investigate how neurodegenerative disease develops differently from person to person and how patients might respond to particular treatments.

"At Mount Sinai we are creating and cryopreserving miBrains from patients," Dr. Blanchard added. "This will enable personalized studies into how neurodegenerative disease develops and how individuals may respond to therapies. By enabling potential therapies to be tested earlier and more efficiently, the miBrain platform could help bridge the gap between laboratory discoveries and treatments for a broad range of disorders."

Study Funding

The Cell study examining vascular degeneration in the brain received support from the National Aeronautics and Space Administration (80ARC022CA004), the National Institute on Aging at the National Institutes of Health (R01AG089533, UH3NS115064, U54AG090669, T32GM146636), The SWT Foundation, and the CureAlz Fund.

The Cell Stem Cell study examining abnormal protein buildup in the brain received support from the National Aeronautics and Space Administration (80ARC022CA004), Aligning Science Across Parkinson's (ASAP-024297) through the Michael J. Fox Foundation for Parkinson's Research, the National Institute of Neurological Disorders and Stroke and the National Institute on Aging at the National Institutes of Health (R01NS114239, UH3NS115064, 1U54AG090669-01, T32AG04968, F31NS13090), the CureAlz Fund, and The SWT Foundation.