A variant of the apolipoprotein E gene that is a genetic risk factor for Alzheimer's disease.
MIT researchers used a genome-wide CRISPR screen to tie APOE4's myelin damage to suppressed Wnt signaling in human oligodendrocytes. The result gives drug researchers a named pathway to test, though the evidence so far comes from cultured cells and mice.
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Joel Blanchard's Mount Sinai team reports in Cell that APOE4 pushes brain vessel cells toward a scar-producing state in lab-grown tissue. In people the evidence is a comparison of cell counts, so the link to amyloid rests on models.
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Mount Sinai researchers report APOE4 turns brain pericytes into scar-making cells, and blocking TGF-beta reversed the change in aged mice. That gives drug developers a vascular target in carriers of the strongest known genetic risk factor for Alzheimer's.
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University of Missouri researchers found four weeks of daily low-dose rapamycin raised brain blood flow only in healthy APOE4 carriers aged 45 to 65. That makes perfusion a measurable target for prevention trials, though a month of scans cannot show that fewer people go on to develop dementia.
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Mount Sinai researchers report that APOE4 turns vessel-support cells into scar-forming ones, and that blocking TGF-beta reversed it in aged mice. Both reversals so far are in aged mice and in stem-cell-derived human tissue.
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