Interactions of beta-amyloid (A beta) peptides with neuronal membranes have been associated with the pathogenesis of Alzheimer's disease (AD); however, the molecular details remain unclear. We used atomistic molecular dynamics (MD) simulations to study the interactions of A beta(40) and A beta(42) with model neuronal membranes. The differences between cholesterol-enriched and depleted lipid domains were investigated by the use of model phosphatidylcholine (PC) lipid bilayers with and without 40 mol % cholesterol. A total of 16 independent 200 ns simulation replicates were investigated. The surface area per lipid, bilayer thickness, water permeability barrier, and lipid order parameter, which are sensitive indicators of membrane disruption, were significantly altered by the inserted state of the protein. We conclude that cholesterol protects A beta-induced membrane disruption and inhibits beta-sheet formation of A beta on the lipid bilayer. The latter could represent a two-dimensional (2D) seeding template for the formation of toxic oligomeric A beta in the pathogenesis of AD.