Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta-amyloid (A beta) precursor protein containing a Lys(670) --> Asn, Met(671)--> Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in A beta(1-40) and a 14-fold increase in A beta(1-42/43) accompanied the appearance of these behavioral deficits, Numerous A beta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of A beta. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer’s disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.