Neurotoxic amyloid beta peptide (Abeta) accumulates in the brains of individuals 
with Alzheimer disease (AD). The APOE4 allele is a major risk factor for 
sporadic AD and has been associated with increased brain parenchymal and 
vascular amyloid burden. How apoE isoforms influence Abeta accumulation in the 
brain has, however, remained unclear. Here, we have shown that apoE disrupts 
Abeta clearance across the mouse blood-brain barrier (BBB) in an 
isoform-specific manner (specifically, apoE4 had a greater disruptive effect 
than either apoE3 or apoE2). Abeta binding to apoE4 redirected the rapid 
clearance of free Abeta40/42 from the LDL receptor-related protein 1 (LRP1) to 
the VLDL receptor (VLDLR), which internalized apoE4 and Abeta-apoE4 complexes at 
the BBB more slowly than LRP1. In contrast, apoE2 and apoE3 as well as 
Abeta-apoE2 and Abeta-apoE3 complexes were cleared at the BBB via both VLDLR and 
LRP1 at a substantially faster rate than Abeta-apoE4 complexes. 
Astrocyte-secreted lipo-apoE2, lipo-apoE3, and lipo-apoE4 as well as their 
complexes with Abeta were cleared at the BBB by mechanisms similar to those of 
their respective lipid-poor isoforms but at 2- to 3-fold slower rates. Thus, 
apoE isoforms differentially regulate Abeta clearance from the brain, and this 
might contribute to the effects of APOE genotype on the disease process in both 
individuals with AD and animal models of AD.