Epidemiological, animal, and cellular studies suggest that abnormalities in cholesterol metabolism are a risk factor for Alzheimer's disease (AD), potentially by increasing amyloid-β (Aβ) peptide levels. Accumulation of Aβ in the brain is suggested to play a key role in the neurodegenerative processes by triggering the hyperphosphorylation of tau and the neuronal death that develop in the course of AD. However, the mechanisms by which cholesterol increases Aβ levels are still ill-defined. Work from our laboratory using the cholesterol-fed rabbit model system indicates that hypercholesterolemia increases Aβ through multiple mechanisms that affect production, degradation and clearance of this peptide. We also have found that the oxidized cholesterol metabolite, 27-hydroxycholesterol, also increases Aβ levels in organotypic slices from rabbit hippocampus. Our results suggest that multiple signaling pathways are involved in hypercholesterolemia-induced AD pathology and suggest 27-hydroxycholesterol as the link between circulating cholesterol and AD-like pathology in the brain.