Sex differences in brain glucose metabolism and Alzheimer's disease risk and progression

Sex differences are increasingly recognized as central to the biology of Alzheimer's disease (AD), yet the mechanisms through which they shape brain metabolism and disease vulnerability remain incompletely understood. Brain glucose hypometabolism is a core hallmark of AD and emerges decades before clinical decline, but accumulating evidence indicates that its causes, timing, and functional consequences differ between women and men. In this review, we synthesize findings from neuroimaging, molecular, and cellular studies to examine how sex-dependent regulation of glucose transport, glycolysis, and mitochondrial function interacts with aging and AD pathology. We highlight reinforcing evidence for a steeper and more pathology-linked decline in mitochondrial glucose metabolism in females, particularly in the context of menopause and apolipoprotein E (APOE) ε4 genotype. We identify major knowledge gaps at the level of cell type, brain region, and disease stage, and outline priorities for sex-informed, mechanistically anchored research to enable metabolic-precision interventions for AD risk and progression.