Fig. 5: Hypothesis of an APOE4 genotype-dependent metabolic switch from early hyper- to disease-associated hypometabolism.

In young, healthy APOE4 carriers, cellular energy metabolism is elevated, characterized by increased glucose uptake, enhanced glycolysis and elevated lactate release, alongside high mitochondrial respiration. However, over time and with increasing AD pathologies, this state may shift towards decreased energy metabolism, as cells become unable to sustain these processes. This decline may be further exacerbated by the presence of APOE4, further contributing to disease progression. MCT monocarboxylate transporters, MPC mitochondrial pyruvate carrier 2, Glu glucose, GLUT glucose transporter, TCA tricarboxylic acid cycle, Lac lactate.