Understanding ApoE4-induced metabolic shifts in Alzheimer's disease

The ApoE4 allele is the strongest and most prevalent genetic risk factor for late-onset Alzheimer’s disease (AD). How ApoE4 predisposes to AD remains unclear, but considerable evidence suggests this may involve a disruption of energy metabolism. In AD patients and asymptomatic apoE4 carriers regional brain glucose uptake is decreased. ApoE4 is also less efficient in lipid transport and can directly impair mitochondrial respiration. However, we don’t understand why these changes in energy metabolism occur, or how they contribute to neurodegeneration. We also don’t know how the changes in glucose uptake and mitochondrial function relate to each other. Our long-term goal is to understand how ApoE4 disrupts energy metabolism, and then to target energy metabolism therapeutically. To gain insight into how ApoE4 changes glucose and energy metabolism, we developed innovative assays to measure the balance between glycolysis and respiration in mouse models and in patients. With this approach, we can test our central hypothesis that ApoE4’s effects on neuronal respiration leads to metabolic rewiring and the production of toxic metabolites that contribute to disease pathophysiology. The objective of this proposal is to determine the cellular and molecular basis by which ApoE4 reprograms brain energy metabolism from respiration towards glycolysis and increased toxic metabolites, and to characterize these changes in human patients. We will accomplish this objective in two specific aims. (1) We will use live imaging and mass spectrometry to measure metabolic fluxes, and determine how ApoE4 disrupts energy metabolism and toxic metabolites in mice. (2) We will use magnetic resonance spectroscopic imaging to assess if ApoE4 rewires brain energy metabolism and increases toxic metabolites in human subjects with normal cognitive function as well as those with early AD. These studies will provide some of the first insights into how ApoE4 disrupts the critical brain energy balance between respiration and glycolysis and rewires metabolism in live mice and humans. The results could provide new insights into disease pathophysiology, and identify biomarkers that could inform AD subtypes and progression. Project Number: 1R01AG093939-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: KEN NAKAMURA | Institution: J. DAVID GLADSTONE INSTITUTES, SAN FRANCISCO, CA | Award Amount: $801,193 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 AN-W (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11320682