Differential Effect of APOE Alleles on Brain Glucose Metabolism in Targeted Replacement Mice: An [(18)F]FDG-μPET Study

BACKGROUND: The Apolipoprotein E (ApoE) alleles ɛ2, ɛ3, and ɛ4 are known to differentially modulate cerebral glucose metabolism and the risk for Alzheimer’s disease (AD) via both amyloid-β (Aβ)-dependent and independent mechanisms. OBJECTIVE: We investigated the influence of ApoE on cerebral glucose metabolism in humanized APOE Targeted Replacement (TR) mice at ages that precede the comparison of Aβ parenchymal deposits in APOE4-TR mice. METHODS: Fludeoxyglucose ([(18)F]FDG) positron emission tomography (PET) measures were performed longitudinally in homozygous APOE-TR mice (APOE2, APOE3, APOE4; n = 10 for each group) at 3, 5, 11, and 15 months. Results were quantified using standard uptake values and analyzed statistically using a linear mixed effects model. Levels of the Aβ(40) and Aβ(42) peptides were quantified ex vivo using enzyme-linked immunosorbent assay (ELISA) at 15 months in the same animals. RESULTS: APOE2 mice (versus APOE3) showed a significant increase in glucose metabolism starting at 6 months, peaking at 9 months. No evidence of hypometabolism was apparent in any region or time point for APOE4 mice, which instead displayed a hypermetabolism at 15 months. Whole brain soluble Aβ(40) and Aβ(42) levels were not significantly different between genotypes at 15 months. CONCLUSIONS: Introduction of human APOE alleles ɛ2 and ɛ4 is sufficient to produce alterations in brain glucose metabolism in comparison to the control allele ɛ3, without a concomitant alteration in Aβ(40) and Aβ(42) levels. These results suggest novel Aβ-independent metabolic phenotypes conferred by ɛ2 and ɛ4 alleles and have important implications for preclinical studies using TR-mice.