Fig. 8.

Working model. Glucose hypometabolism occurs with aging, possibly due to the accumulation of glycolysis intermediate glucose-6-phosphate, thereby causing feedback inhibition on rate-limiting glycolysis enzyme hexokinase via the dissociation of hexokinase from mitochondrial VDAC. This glucose hypometabolism is further exacerbated by a decline in synaptic complex I function in the cortex of female AD mice. Impaired glycolysis forces a metabolic shift toward fatty acid and ketone metabolism that corresponds with increased non-synaptic (astrocyte-enriched) mitochondrial complex II function of the cortex and hippocampus of female AD mice. In contrast, male synaptic complex I function is preserved, and augmented complex IV respiration is observed. Decreased mitochondrial function combined with impaired purine biosynthesis and polymerase β deficiency drives synaptic complex I impairment in the hippocampus contributing to energy failure and eventual hippocampal atrophy. These metabolic mechanisms of glucose hypometabolism likely contribute to an increased AD risk in woman compared to men