IGF-1 receptor (IGF-1R) expression is enriched in brain endothelial cells.8–10 Notably, the brain vasculature is unusually resistant to cholesterol transit, both via passive leakage between endothelial cells and active trans-endothelial transit.23,24 Here, we show that ApoE−/− mice with transgenic over-expression of human IGF-1R in the endothelium (hIGFREO/ApoE−/−) have reduced atherosclerosis with reduced paracellular vascular leakage and cellular cholesterol uptake. The gene discussed is APOE; the disease is atherosclerosis.