bioRxiv posted October 20, 2020.
APOE4 Lowers Energy Expenditure and Impairs Glucose Oxidation by Increasing Flux through Aerobic Glycolysis
Brandon C Farmer, ..., Lance A. Johnson
For those who like to speculate, the study's findings provide a neat "just so" story in which APOE4 was adaptive for our hunting & gathering ancestors, who were subject to periodic food shortages, which would have been particularly acute when burdened by a significant parasite load (as was most likely the case). This would have been especially true for females going through the energy demands of pregnancy.
I guess the takeaway is that we want to find ways to improve oxygen consumption in our brains. (Which is something that has already been discussed a lot in the group.)
Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer’s disease (AD), as well as in young cognitively normal carriers of theΕ4allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.
Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggested an E4 associated increase in aerobic glycolysis (i.e. the Warburg effect). ...
... young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis. Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a ‘Warburg like’ endophenotype that is observable in young humans decades prior to clinically manifest AD.