Researchers at Mount Sinai have traced a specific mechanism by which APOE4, the strongest known genetic risk factor for Alzheimer's disease, damages the brain's blood vessels and encourages abnormal protein buildup. The work, published in Cell and Cell Stem Cell, points to disease processes that appear to be reversible, at least in laboratory models.
The vascular side of Alzheimer's has been a longstanding puzzle. Scientists have known for years that small blood vessels in the brain deteriorate as the disease advances, and that this deterioration is more pronounced in people carrying APOE4. Without a clear mechanism, though, that damage was often treated as fallout from the disease rather than something driving it forward. Alzheimer's affects more than 7 million older adults in the United States.
For the Cell study, published September 24, the Mount Sinai team pooled existing datasets into a single-cell transcriptomic atlas of the human brain vasculature - essentially a map of which genes are switched on in the cells that build and support blood vessels. Using that map, they found that APOE4 pushes pericytes, the cells that wrap and stabilize small vessels and help maintain the blood-brain barrier, into becoming scar-forming myofibroblast-like cells. That shift drove fibrosis in the vessel walls and increased amyloid accumulation around the vessels, a combination likely to compromise blood flow and set the stage for neurodegeneration.
The more encouraging result came next. Blocking TGF-beta signaling, a pathway that governs cell communication and tissue remodeling, restored pericyte coverage and reduced both the fibrosis and the vascular amyloid. The team repeated the experiment in aged APOE4 mice and saw the same reversal, suggesting that APOE4-linked vascular degeneration is not necessarily a one-way process. The companion work also demonstrates a stem cell-derived human brain tissue platform intended to speed up this kind of mechanistic research and early drug development.