- Background: Type 2 diabetes is a risk factor for Alzheimer disease (AD) and several studies have shown that insulin signalling is impaired in AD brain. Progressive brain hypometabolism is a hallmark of AD and can be evaluated using [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET). Peripheral insulin resistance (IR) also increases AD risk. Recent evidence suggests that peripheral IR is associated with significantly lower regional cerebral glucose metabolism in elderly individuals at risk for AD and also predicts medial temporal hypometabolism in AD patients. In this study we evaluated the relationship between IR and cerebral glucose metabolic rate measured by FDG-PET with arterial input in a population of non-diabetic AD subjects. Methods: 131 AD subjects form the Evaluating Liraglutide in Alzheimer's Disease (ELAD) trial (NCT01843075) were enrolled. Glucose and insulin levels were measured after a 4-hour fast on the day of the visit for the FDG-PET scan. Insulin resistance was calculated by both the homeostatic model assessment (HOMA-IR) and the modified HOMA2 calculator. For [18F]FDG analysis, both rCMRGlc parametric images were generated (using spectral analysis with an arterial plasma input function), as well as [18F]FDG ratios, calculated by dividing each target region cortical ROI value by the median value in the pons. Results: In this non-diabetic AD population, the prevalence of IR was about 16%. Subjects above and below the cut-off values for IR (2.9 for HOMA-IR and 1.7 for HOMA2) did not show significant differences in terms of cerebral glucose metabolism, cognitive measures and demographic characteristics. No significant correlation was observed between peripheral IR calculated by either HOMA-IR or HOMA2 and rCMRGlc or ROI uptake of [18F]FDG. Conclusions: In this study of non-diabetic AD population with invasive measurement of cerebral glucose metabolic rate, we have demonstrated that peripheral insulin resistance does not correlate with cerebral glucose metabolism and thus it does not represent a good measure of central insulin resistance.