Alzheimer's disease (AD) is a progressive neurodegenerative dementia characterized by amyloid plaque accumulation, synapse/dendrite loss, and cognitive impairment. Transgenic mice expressing mutant forms of amyloid-beta precursor protein (AbetaPP) and presenilin-1 (PS1) recapitulate several aspects of this disease and provide a useful model system for studying elements of AD progression. AbetaPP/PS1 mice have been previously shown to exhibit behavioral deficits and amyloid plaque deposition between 4-9 months of age. We crossed AbetaPP/PS1 animals with mice of a mixed genetic background (C57BL/6 × 129/SvJ) and investigated the development of AD-like features in the resulting outcrossed mice. The onset of memory-based behavioral impairment is delayed considerably in outcrossed AbetaPP/PS1 mice relative to inbred mice on a C57BL/6 background. While inbred AbetaPP/PS1 mice develop deficits in radial-arm water maze performance and novel object recognition as early as 8 months, outcrossed AbetaPP/PS1 mice do not display defects until 18 months. Within the forebrain, we find that inbred AbetaPP/PS1 mice have significantly higher amyloid plaque burden at 12 months than outcrossed AbetaPP/PS1 mice of the same age. Surprisingly, inbred AbetaPP/PS1 mice at 8 months have low plaque burden, suggesting that plaque burden alone cannot explain the accompanying behavioral deficits. Analysis of AbetaPP processing revealed that elevated levels of soluble Abeta correlate with the degree of behavioral impairment in both strains. Taken together, these findings suggest that animal behavior, amyloid plaque deposition, and AbetaPP processing are sensitive to genetic differences between mouse strains. J. Comp. Neurol., 521:1395-1408, 2013. © 2012 Wiley Periodicals, Inc. PUBLICATION ABSTRACT