ABSTRACT Metabolic disorders (i.e. obesity, prediabetes or type 2 diabetes), often resulting from poor diet, is a significant risk factor for Alzheimer’s disease (AD). Several common neurodegenerative mechanisms in these two conditions have been identified, including oxidative stress, mitochondrial dysfunction, and inflammation. Changes in metabolism and mitochondrial bioenergetics may be at the heart of both metabolic disorders and AD but may be affecting men and women differently. Although AD treatments exist, none are very effective, and certainly no drugs are sex-specific, creating a significant unmet medical need. Interestingly, several clinical trials testing nilotinib, a repurposed leukemia drug, have shown promise for use in treating AD and other neurodegenerative diseases. In addition to attenuating hallmark pathology, we recently demonstrated that nilotinib improves mitochondrial function and bioenergetics in cultured cells from the 3xTg-AD mouse model for AD. In this study, our specific objective is to use a high fat diet (HFD) to model metabolic disease in 3xTg-AD mice and evaluate sex-differences associated with bioenergetic, cognitive, and neuropathological outcomes, as well as whether nilotinib can improve them. The rationale for the proposed work is further supported by a recent phase II study conducted by our collaborator, Dr. Scott Turner, that showed 12 months of treatment with nilotinib, at 150 mg/day for 26 weeks followed by 300 mg/day for 26 weeks was safe, tolerable, and effective in patients with mild to moderate AD. Here, we hypothesize that nilotinib will improve mitochondrial bioenergetics, enhance cognitive function, and reduce biomarkers of AD pathology in a sex-dependent manner in 3xTg-AD mice subjected to a HFD. In Aim 1, we will determine whether in vivo treatment (100 or 250 mg/kg for 2 months) with nilotinib improves mitochondrial function and bioenergetics in 3xTg-AD mice in the absence and presence of HFD-induced metabolic disease