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About two-thirds of those with Alzheimer's disease (AD) are women, most of whom are post-menopausal. Menopause accelerates the risk for dementia by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (e.g. obesity, diabetes, or prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. The goal of this study was to determine the effects of menopause and high fat diet on metabolic outcomes in the AppNL-F knock-in mouse model of Alzheimer's disease. To model menopause, we used an accelerated ovarian failure model (4-vinylcyclohexene diepoxide, VCD). This ovary-intact model is more clinically relevant than an ovariectomy model, as mice go through a perimenopausal period. At 3 months of age, AppNL-F mice were administered VCD or vehicle (oil) and then placed on either a control diet (10% fat) or a high fat diet (HF; 60% fat) and maintained on the diets until 10 months of age. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. Menopause had independent effects on some serum metabolic health biomarkers (insulin) and synergic effects with HF diet on other markers (glucagon). Some metabolic effects of menopause may be centrally mediated, as menopause altered the expression of hypothalamic genes related to energy balance and increased microgliosis in the lateral hypothalamic nucleus. This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further …