Susceptibility to Alzheimer's disease (AD) is governed by multiple genetic factors. Remarkably, the LDL receptor-related protein (LRP) and its ligands, apoE and alpha 2M, are all genetically associated with AD. In this study, we provide evidence for the involvement of the LRP pathway in amyloid deposition through sequestration and removal of soluble amyloid beta -protein (A beta). We demonstrate in vitro that LRP mediates the clearance of both A beta 40 and A beta 42 through a bona fide receptor-mediated uptake mechanism. In vivo, reduced LRP expression is associated with LRP genotypes and is correlated with enhanced soluble A beta levels and amyloid deposition. Although LRP has been proposed to be a clearance pathway for A beta, this work provides the first in vivo evidence that the LRP pathway may modulate A beta deposition and AD susceptibility by regulating the removal of soluble A beta.