Metabolic dysfunction, arising from impaired glucose metabolism and mitochondrial dysfunction, and neuronal network hyperexcitability are key age-related alterations postulated to be involved in Alzheimer’s disease (AD) pathogenesis. Mark Mattson, PhD, Johns Hopkins University School of Medicine, Baltimore, MD, outlines our understanding of these changes, what underlies them, and how boosting ketone levels is an interesting therapeutic approach to target these alterations. It is thought that when starved of glucose, neurons can still use ketones as an energy source and thus, using intermittent fasting to increase ketone levels may be beneficial. In AD mouse models treated with a dietary restriction regimen, researchers have seen increased resistance to degeneration of hippocampal neurons, delayed onset of cognitive impairment, and reduced Alzheimer’s neuropathology. Supplementing the diet of these mice with a ketone ester suppressed hyperexcitability, prevented seizure development, and enhanced GABA tone. This interview took place at the Alzheimer's Association International Conference (AAIC) 2022 in San Diego, CA.