AbstractBack-translation of clinical imaging biomarkers of Alzheimer’s disease (AD), such as alterations in cerebral glucose metabolism detected by [¹⁸F]FDG positron emission tomography (PET), would be valuable for preclinical studies evaluating new disease-modifying drugs for AD. However, previous confounding results have been difficult to interpret due to differences in mouse models and imaging protocols between studies. We used an equivalent study design and [¹⁸F]FDG µPET imaging protocol to compare changes in cerebral glucose metabolism in commercial transgenic APP_Swe-PS1_dE9 (n = 12), Tg2576 (n = 15), and wild-type mice (n = 15 and 9). Dynamic [¹⁸F]FDG scans were performed in young (6 months) and aged (12 or 17 months) mice and the results verified by ex vivo methods (i.e., tissue counting, digital autoradiography, and beta-amyloid and Iba-1 immunohistochemistry). [¹⁸F]FDG uptake exhibited significant regional differences between genotypes (TG < WT) and ages (6 months <12 months) in the APP_Swe-PS1_dE9 model, whereas similar differences were not present in Tg2576 mice. In both models, only weak correlations were detected between regional beta-amyloid deposition or microgliosis and [¹⁸F]FDG uptake. By using equivalent methodology, this study demonstrated differences in cerebral glucose metabolism dysfunction detected with [¹⁸F]FDG PET between two widely used commercial AD mouse models.