Tech & Science
Mount Sinai Finds Reversible Alzheimer's Vessel Damage
Mount Sinai scientists reveal how the APOE4 gene variant drives blood vessel damage and protein accumulation in Alzheimer's disease, identifying potential therapeutic targets.
Researchers at Mount Sinai have identified how the APOE4 genetic variant, recognized as the strongest hereditary risk factor for Alzheimer’s disease, causes damage to brain blood vessels and promotes the buildup of harmful proteins. These findings challenge previous assumptions that vascular injury was merely a late-stage consequence of the condition, suggesting instead that it is an active biological process driven by genetics.
How APOE4 Drives Vascular Scarring
The team published two studies in the journals Cell and Cell Stem Cell, detailing pathological mechanisms that may be therapeutically reversible. The first study focused on creating a single-cell transcriptional atlas of human brain blood vessels, mapping the genetic activity within cells that form and support these structures. Scientists discovered that APOE4 transforms pericytes—cells responsible for stabilizing small vessels and maintaining the blood-brain barrier—into myofibroblast-like cells that generate scar tissue.
This transformation increases vascular fibrosis and amyloid accumulation around blood vessels, potentially impairing blood flow and accelerating neurodegeneration. Crucially, blocking TGF-β signaling, a pathway involved in cell communication and tissue remodeling, restored pericyte coverage and reduced both fibrosis and vascular amyloid. These results were replicated in aged APOE4 mice, confirming the potential for reversing these effects through treatment.
Joel Blanchard, a co-author of the study, stated that vascular damage is not a delayed outcome of Alzheimer’s but an active process caused by APOE4 that could be reversible. He noted that the findings reveal new therapeutic targets, emphasizing that APOE4 does more than increase risk; it actively converts supportive brain cells into scar-forming entities.
Cholesterol Disrupts Protein Clearance
The second study utilized miBrains, three-dimensional human brain tissues derived from induced stem cells containing all major brain cell types. This platform revealed that APOE4 leads to cholesterol accumulation in astrocytes, disrupting the lysosomal waste disposal system. Lysosomes are cellular organelles essential for breaking down waste products.
The disruption reduces the ability of astrocytes to break down alpha-synuclein, a protein naturally present in the brain. Instead of being cleared, the protein clumps together and spreads to neurons, forming harmful deposits. The researchers concluded that targeting cholesterol metabolism and lysosomal function offers a promising avenue for treatment. Additionally, the cryopreservable nature of the miBrains platform provides a new tool to accelerate the development of therapies for Alzheimer’s disease.
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