Mice co-expressing the Swedish amyloid precursor protein mutation (APP(Swe)) and exon 9 deletion (DeltaE9) of the PSEN1 gene begin to develop amyloid plaques at 6-7 months of age. We demonstrate here a spatial learning deficit in 7-month-old APP(Swe) + PSEN1DeltaE9 bigenic mice using an adaptation of the Barnes maze. Mice were first trained on a cued target followed by a hidden-target condition. Although bigenic mice quickly learned the cued-target version of the task, they were significantly impaired when switched to the hidden-target version. In contrast, a separate group of double-transgenic mice trained first on the spatial hidden-target version of the task were unimpaired relative to wild-type controls. We propose that processes such as general rule learning, context learning and exploratory habituation exert a greater influence when the testing environment is novel and overshadow the spatial memory deficit in naive bigenic mice. However, when cued-target training is conducted first, these processes habituate and the spatial learning deficit is unmasked. Seven-month-old APP(Swe) + PSEN1DeltaE9 mice were unimpaired on tests of memory that did not involve learning the rules governing spatial associations.