Project Summary / Abstract Cognitive dysfunction and dementia rates are increasing worldwide in part due to the significant increase in life expectancy. Alzheimer’s disease (AD), the main cause of dementia, is a progressive neurodegenerative brain disease characterized by impairments in cognitive function. Aging is the main risk factor for AD and unfortunately there is no effective treatment for slowing down aging or treating AD. Current approaches to treat AD (e.g., amyloid beta accumulation and tau hyperphosphorylation) have been unsuccessful which calls for novel approaches to treat the full spectrum of this disease. Recent studies have postulated that cognitive decline and AD might be manifestations of metabolic disorders. In particular, changes in glucose metabolism and brain insulin sensitivity have been identified as common features observed in AD. Our published works reveal that the endocrine hormone fibroblast growth factor 21 (FGF21) decreases body weight during obesity, improves insulin sensitivity, and corrects metabolic dysfunctions in animal models. Clinical trials with FGF21 mimetics have also demonstrated the efficacy of targeting this pathway to improve metabolic profiles in humans. Interestingly, recent data suggests that FGF21 administration may also prevent neurodegeneration and pathological deficits in animal models of AD. While circulating FGF21 levels are derived primarily by the liver, our recently published study reveals the unexpected discovery that FGF21 is also expressed in a very specific region of the central nervous system. Specifically, FGF21 is expressed in the retrosplenial cortex and can signal to the hippocampus and can regulate learning and memory. A previous study demonstrates that FGF21 is induced from neurons in response to mitochondrial stress. These observations are the backbone of our main hypothesis in this proposal which seeks to interrogate whether FGF21 signals to neurons in hippocampus to not only improve neuronal metabolism and memory, but also improves AD symptoms. This proposal employs various genetic AD mouse models to explore different aspects of AD, as well as genetic and pharmacological approaches, to investigate the effects of FGF21 and in the improvement of memory and cognition. Together, these studies will not only further our knowledge of the role of FGF21 in neuronal metabolism but will also provide a better understanding of potential metabolic abnormalities during AD. Finally, these studies may reveal a potential therapeutic approach to treat AD and its related dementias.