Insulin resistance, a major symptom of type-2 diabetes mellitus (T2DM), is a known risk factor for Alzheimer’s disease (AD). Emerging evidence has shown that both diseases share similar pathophysiology which includes amyloidogenesis and cognitive decline. In the present study, we aimed to understand how T2DM or related conditions contribute to AD pathogenesis. We used the AppNL-F/NL-F knock-in mouse model of AD, which contains a humanized Aβ region along with two pathogenic mutations, the Swedish “NL” and the Iberian “F” to express APP at wild-type levels while producing elevated pathogenic Aβ. AppNL-F/NL-F mice recapitulate several AD-associated pathologies, including amyloid plaques in the cortex and hippocampus, and show signs of very mild cognitive impairment at 18 months of age, but avoid potential artifacts introduced by APP transgene. For this study, 6-month-old AppNL-F/NL-F and wild-type male mice were fed with a regular diet (RD) or high-fat diet (HFD) for 12 consecutive months. We then compared the effects of the diet on the AD.