BACKGROUND: In Alzheimer's disease (AD), alterations in metal homeostasis, including the accumulation of metal ions in the plaques and an increase of iron in the cortex, have been well documented but the mechanisms involved are poorly understood. OBJECTIVE: In this study, we compared the metal content in the plaques and the iron speciation in the cortex of three mouse models, two of which show neurodegeneration (5xFAD and Tg-SwDI/NOS2-/- (CVN) and one that shows very little neurodegeneration (PSAPP). METHODS: The Fe, Cu, and Zn contents and speciation were determined using synchrotron X-ray fluorescence microscopy (XFM) and X-ray absorption spectroscopy (XAS), respectively. RESULTS: In the mouse models with reported significant neurodegeneration, we found that plaques contained ~25% more copper compared to the PSAPP mice. The iron content in the cortex increased at the late stage of the disease in all mouse models, but iron speciation remains unchanged. CONCLUSIONS: The elevation of copper in the plaques and iron in the cortex is associated with AD severity, suggesting that these redox-active metal ions may be inducing oxidative damage and directly influencing neurodegeneration.