Genetic causes of Alzheimer's disease (AD) include mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes. The mutant APP(K670N,M671L) transgenic line, Tg2576, shows markedly elevated amyloid β-protein (Aβ) levels at an early age and, by 9-12 months, develops extracellular AD-type Aβ deposits in the cortex and hippocampus. Mutant PS1 transgenic mice do not show abnormal pathology, but do display subtly elevated levels of the highly amyloidogenic 42- or 43-amino acid peptide Aβ42(43) (ref. 3). Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1(M146L) transgenic line develop large numbers of fibrillar Aβ deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 littermates. In the period preceding overt Aβ deposition, the doubly transgenic mice show a selective 41% increase in Aβ42(43) in their brains. Thus, the development of AD-like pathology is substantially enhanced when a PS1 mutation, which causes a modest increase in Aβ42(43), is introduced into Tg2576-derived mice. Remarkably, both doubly and singly transgenic mice showed reduced spontaneous alternation performance in a 'Y' maze before substantial Aβ deposition was apparent. This suggests that some aspects of the behavioral phenotype in these mice may be related to an event that precedes plaque formation.