Alzheimer's disease (AD) is a multigenic neurodegenerative disorder characterized by distinct neuropathological hallmarks including deposits of the β-amyloid (Aβ) peptide. Aβ is a 39- to 43-amino acid peptide derived from the proteolytic processing of the amyloid precursor protein (APP). While increasing evidence suggests that altered APP processing and Aβ metabolism is a common feature of AD, the relationship between the levels of Aβ and various APP products and the onset of AD remains unclear. We have undertaken a screen to characterize genetic factors that modify APP processing, Aβ metabolism and Aβ deposition in a genomic-based yeast artificial chromosome (YAC) transgenic mouse model of AD. A mutant human APP YAC transgene was transferred to three inbred mouse strains. Despite similar levels of holo-APP expression in the congenic strains, the levels of APP C-terminal fragments as well as brain and plasma Aβ in young animals varied by genetic background. Furthermore, we demonstrate that age-dependent Aβ deposition in the APP YAC transgenic model is dramatically altered depending on the congenic strain examined. These studies demonstrate that APP processing, Aβ metabolism and Aβ deposition are regulated by genetic background and that analysis of these phenotypes in mice should provide new insights into the factors that regulate AD pathogenesis.