Alzheimer's blood vessel damage mechanism
A recent study from Mount Sinai has revealed that the genetic variant APOE4, the strongest hereditary risk factor for Alzheimer’s disease, actively causes damage to brain blood vessels and promotes the accumulation of harmful proteins, rather than being merely a consequence of the disease as previously believed. The research showed that APOE4 transforms supportive cells in the vasculature—such as surrounding cells and small vessels—into scar-forming cells, which enhances fibrosis and amyloid buildup, affecting blood flow and accelerating neurodegeneration. These effects can be reversibly treated by blocking the TGF-β pathway, which reduces fibrosis and restores blood vessel function—a strategy demonstrated successfully in aged mice carrying APOE4. Additionally, a second study found that APOE4 causes cholesterol to accumulate in star-shaped brain cells (astrocytes), disrupting their waste clearance system and leading to the buildup of the harmful protein alpha-synuclein, which forms deposits that damage brain cells. These findings open new avenues for developing treatments targeting cholesterol metabolism and improving lysosomal function, utilizing three-dimensional human brain tissue derived from stem cells. This approach enhances the potential for personalized therapies and faster testing of new interventions.
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