The pathogenesis of Alzheimer's disease (AD) is complex involving multiple contributing factors. The extent to which AD pathology affects the metabolome is still not understood nor is it known how disturbances change as the disease progresses. For the first time, we have profiled longitudinally (6, 8, 10, 12, and 18 months) both the brain and plasma metabolome of APPswe/PS1deltaE9 double transgenic and wild-type mice. A total of 187 metabolites were quantified using a targeted metabolomic methodology. Multivariate statistical analysis produced models that distinguished APPswe/PS1deltaE9 from wild-type mice at 8, 10, and 12 months. Metabolic pathway analysis found perturbed polyamine metabolism in both brain and blood plasma. There were other disturbances in essential amino acids, branched-chain amino acids, and also in the neurotransmitter serotonin. Pronounced imbalances in phospholipid and acylcarnitine homeostasis were evident in 2 age groups. AD-like pathology, therefore, affects greatly on both the brain and blood metabolomes, although there appears to be a clear temporal sequence whereby changes to brain metabolites precede those in blood.