SUMMARY Aging is the most powerful risk factor for Alzheimer’s disease (AD), and it contributes to the odds of type-2 diabetes mellitus (T2D) as well. Aging is also associated with a decline in the brain’s use of glucose, its most important fuel. Astrocytes play a key role in shuttling glucose from the bloodstream to where it is needed by the neuronal units of activity deeper in the brain tissue. We find evidence of a defect in a key glucose transport molecule of astrocytes in AD and in male mice of a line genetically modified to reproduce some aspects of AD. Though the females also overproducing the β-amyloid peptide (Aβ), only males exhibit dysregulation of circulating glucose, a decline in brain glucose usage, and spatial memory deficits. Human females have a higher incidence of AD, but this is manifest after menopause, which mice do not experience. This suggests that the female mice may be protected by sex-specific hormones such as estrogens. This supplement will test this hypothesis by examination of female Aꞵ-expressing mice that have had their ovaries removed, and the role of estrogen will be determined by adding this hormone back to some of the females. Peripheral glucose regulation, brain glucose usage, and memory behavior will be tested to determine if loss of estrogens puts the female mice at risk the same deficits seen in males. Because differences in the gene for apolipoprotein E (ApoE) affect the risk for AD in a sex-dependent way, we will also assay the parameters above in mice that have been genetically engineered to express two variants of human ApoE. These studies thus explore a novel hypothesis about a specific element of energy utilization as it pertains to the aging brain and its connection to sex-related risks. As such, the project may provide innovative strategies for therapeutic intervention.