Insulin resistance is a common shared feature in Alzheimer’s disease (AD) and metabolic dysfunction-associated steatotic liver disease (MASLD), and recent studies have found that MASLD patients have almost 2-fold higher rates of dementia than a matched cohort. Still, it remains unknown how MASLD impacts AD pathogenesis on a mechanistic level. A key feature driving insulin resistance is inflammation in metabolic organs, involving macrophages and pro-inflammatory cytokines that reduce glucose metabolism. Inflammation is also characteristic of the AD brain, and our goal is to delineate the role of peripheral insulin resistance and inflammation in the neurodegeneration of the aging brain. Our preliminary study found that mice lacking interferon- (IFN) signaling in myeloid cells are rescued from obesity-mediated insulin resistance and inflammation in the liver, suggesting a possible role for macrophage-derived factors in MASLD. Interleukin-12 (IL-12), a pro-inflammatory cytokine secreted by macrophages, is elevated in aging and obesity, and we made a novel observation that IL-12 causes insulin resistance by impairing insulin signaling in the liver. Interestingly, systemic loss of the IL-12 subunit has been shown to attenuate AD-like pathology and cognitive decline in the APP/PS1 mice, a model of AD. Together, these data suggest that macrophages and cytokines are critical in MASLD and AD. We will test whether insulin resistance and inflammation in the liver impact AD-relevant neurodegeneration and whether liver macrophages and cytokines play a key role in this biology. Aim 1 will define age-related changes in metabolism and inflammation in peripheral organs and the brain during AD-relevant neurodegeneration in APP/PS1 mice. We will measure organ-specific metabolism using a hyperinsulinemic- euglycemic clamp and labeled metabolites, analyze cellular inflammation using molecular approaches, including MERFISH as a spatial transcriptomic approach, and correlate with AD-relevant phenotypes, including brain plaque load, reactive gliosis, and learning and memory deficits. While descriptive in nature, the results will map previously unknown connections between age-related metabolic and inflammatory events in the liver and similar events in the brain, as necessary first steps toward subsequent mechanistic work. Aim 2 will delineate the liver- brain connection by manipulating the macrophage IFN-IL12 axis to modulate inflammatory and metabolic pathways in the liver and examine its impact on AD-relevant neurodegeneration. We will use a gain or loss-of- function of IFN and IL-12 to test how modifying liver metabolism impacts AD pathologies in APP/PS1 mice. These are critical studies to determine the impact of altered immunity and metabolism in the liver on neurodegeneration, establishing a molecular link between metabolic liver disease and AD. Overall, our aims will test a paradigm-shifting hypothesis that age-related liver insulin resistance and inflammation a...