This Administrative Supplement is in response to NOT-AG-20-034, entitled ‘Alzheimer’s-focused administrative supplements for NIH grants that are not focused on Alzheimer’s disease’. The overall goal of this supplement is to use our existing award, focused on how diabetes-dependent disruption of the circadian clock contributes to the adverse effects of diabetes on the heart, as the platform to assess the impact of these factors on Alzheimer’s disease (AD) and its related dementias (ADRD). The parent application tests the hypothesis that changes in the modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) during diabetes impairs circadian regulation of autophagy/mitophagy in cardiac dysfunction. Interestingly, circadian dysregulation, diabetes, perturbation of protein O-GlcNAcylation, mitochondrial dysfunction and autophagy/mitophagy have also all been linked to AD. It is currently unknown whether 1) O-GlcNAcylation, mitophagy, and mitochondrial function in the brain are circadian regulated and affected by diabetes; and 2) whether circadian, O-GlcNAc and mitophagy manipulations change cognition and neuropathology. Thus our current supplement application will test the hypothesis that AD and ADRD related neurological and pathological phenotypes are a consequence of dysregulation of the circadian clock-O-GlcNAcylation axis resulting in impaired neuronal mitophagy and bioenergetics that is exacerbated by T2DM. The same mouse genetic and pharmacological manipulations, parallel histology and biochemical methods will be used in the brain in the supplement project, as described in the parent project. We will perform studies with the following 2 aims: 1) Determine whether the circadian regulation of O-GlcNAcylation, mitophagy and mitochondrial function in the brain, as well as cognition and neuropathology, are affected by diabetes; and 2) Determine whether genetic perturbation of mitophagy, pharmacological enhancement of mitophagy, and pharmacological perturbation of circadian clock affect O-GlcNAcylation, mitophagy, mitochondrial function, cognition and neuropathology. The goal is to gain new fundamental insights into aspects of circadian disruption and diabetes in the pathogenesis of AD, which have not been investigated previously. New insights gained from this study will help identify innovative approaches for alleviating cognitive and neuropathological deficits in AD.