Project summary Despite great advances in understanding the pathogenesis of Alzheimer's disease and its related dementias (ADRD), effective treatments still remain elusive and most promising therapies have failed to translate from animal models into humans. While cerebral hypometabolism has long been a hallmark of AD, it has been predominantly considered a consequence of neuronal loss and synaptic failure. Relatively little attention has been paid to the potential impact of changes in cerebral energy metabolism early in the pathogenesis of disease despite compelling epidemiological evidence that obesity, insulin resistance, and type 2 diabetes are all risk factors for the development of neurodegenerative diseases such as Alzheimer's disease. We have recently shown that obesity and higher levels of non-esterified fatty acids (NEFA) are associated with blunted cerebral glucose transport. APOE genotype is one of the primary risk factors for AD. Given the important role that APOE has in lipid homeostasis in the periphery and the brain and the fact that several studies have shown that APOE4 carrier status directly affects fatty acid metabolism, the goals of this R21 are to determine whether and how APOE status can modulate the relationships between obesity, NEFA, and brain glucose transport. The findings from these studies will have important implications for ADRD. The central hypothesis is that cognitively normal, relatively young individuals who carry at least one APOE4 allele will have decreased cerebral glucose transport capacity measured using 1H magnetic resonance spectroscopy brain scanning compared to age and BMI matched control subjects who are homozygous APOE3/3 and that this will be potentiated by obesity and exposure to high circulating fatty acids.