Deferoxamine (DFO), injected intramuscularly (IM), was previously shown in clinical trials to reduce the functional decline associated with Alzheimer's disease (AD) by 50% over two years. However, due to side effects and difficulty with administration, DFO treatment was not further developed. Alternatively, DFO has been delivered intranasally (IN) to mice. Specifically, 10 % DFO improved cognition in the P301L tau model of AD and in normal mice, while levels of HIF-1a and pGSK3ß increased. In this study, the effect of IN DFO on the loss of spatial memory and/or accumulation of amyloid in the APP/PS1 transgenic (TG) mouse model of AD was assessed. Mice were treated with a 1% solution of IN DFO or PBS 3x/wk starting at 8 months of age. At 13 months, behavior tests were conducted and brain tissues analyzed. In behavioral tests there both transgenic and a drug effects. In the radial arm water maze, TG-DFO mice had shorter escape latencies and fewer errors than TG-PBS mice in trials 3 and 4 (p<0.05). There were no differences between TG-DFO and WT-PBS mice. In Morris water maze, TG-DFO mice had significantly shorter escape latency and path-length than TG-PBS mice with repeated measures ANOVA (p<0.05). Although the TG mice had significantly more plaques (IHC) and soluble amyloid (ELISA) than WT controls (p>0.05), there was no significant drug effect among TG mice. The decrease in cognitive decline observed with IN DFO treatment is likely related to changes in pathways involving GSK3ß and HIF-1a and not to alterations in amyloid.