Researchers at Mount Sinai have revealed how the APOE4 gene variant, the strongest genetic risk factor for Alzheimer's, causes damage to blood vessels in the brain and the accumulation of harmful proteins.
Alzheimer's disease is known to cause a gradual decline in memory and thinking. Although damage to blood vessels in the brain has long been known, particularly in carriers of the APOE4 gene, its mechanisms have remained unclear, and it was viewed as a later consequence of the disease rather than an active factor in its progression.
The researchers published two studies in the journals Cell and Cell Stem Cell, identifying therapeutically reversible disease mechanisms and providing a new platform for human brain tissue derived from stem cells, with the aim of accelerating the development of treatments.
The first study (from the journal Cell): APOE4 transforms supportive cells into scar-forming cells
Researchers created a single-cell transcriptional atlas of blood vessels in the human brain (a detailed map of gene activity in the cells that form and support blood vessels) and found that APOE4 transforms pericytes, the cells that anchor small vessels and maintain the blood-brain barrier, into scar-forming, myofibroblast-like cells. This promotes vascular fibrosis and amyloid buildup around the vessels, which can impair blood flow and accelerate neurodegeneration.
Most importantly, blocking TGF-β signaling (a pathway involved in cell communication and tissue remodeling) restored the covering of surrounding cells and reduced fibrosis and vascular amyloid, which was reproduced in aged APOE4 mice, demonstrating the potential for reversing these effects therapeutically.
"Blood vessel damage is not a late consequence of Alzheimer's, but a biologically active process caused by APOE4 and potentially reversible," said study co-author Joel Blanchard, adding that the findings "reveal new therapeutic targets."
This study concludes that APOE4 not only increases the risk of Alzheimer's, but also transforms supportive brain cells into scar-forming cells, damaging blood vessels and promoting harmful plaque buildup. However, blocking TGF-β can reverse this process, opening the door to new treatments.
Study 2 (from the journal Cell Stem Cell): Cholesterol disrupts protein elimination
The team used miBrains, three-dimensional human brain tissue derived from induced pluripotent stem cells, containing all the major cell types in the brain. They showed that APOE4 causes cholesterol to accumulate in astrocytes, disrupting the lysosomal waste disposal system (a small organelle within the cell that acts as the cell's waste disposal center) and reducing its ability to break down alpha-synuclein (a protein naturally found in the brain). Instead, the protein clumps together and spreads into neurons, forming harmful deposits.
This second study concludes that APOE4 causes cholesterol buildup in astrocytes, disrupting the waste disposal system and leading to the accumulation of harmful alpha-synuclein. Targeting cholesterol metabolism and lysosome function may be a promising treatment. Furthermore, the cryogenically protected miBrains platform opens the door to personalized medicine and faster treatment testing.
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