Figure 4.

Different modes of glucose metabolism are preferred in the young vs. aging brain. In the young brain, aerobic glycolysis is generally favored, resulting in increased lactate production, presumably by astrocytes, which should be supportive for increased neuronal activity. With aging, there is a shift toward oxidative phosphorylation (OxPhos) instead, resulting in increased electron transport chain (ETC) activity, increased ROS production, and more peroxidated lipids. Healthy cultured cells that are resistant to Aβ toxicity happen to exhibit a preference for aerobic glycolysis, and aerobic exercise, which is known to confer neuroprotection, elevates aerobic glycolysis. In contrast, cells from familial AD patients (PSEN1ΔE9) exhibit elevated OxPhos. While young APOE4 carriers may exhibit increased glycolytic activity, particularly in brain regions associated with AD [e.g., default mode network (DMN), entorhinal cortex], aged APOE4 carriers may exhibit elevated OxPhos instead, although more evidence to demonstrate whether and how such a metabolic shift occurs is warranted.