Higher fasting brain glucose is associated with lower gray matter volume in healthy adults

Glucose hypometabolism is implicated in age-related neurodegeneration, with peripheral markers such as hyperglycemia and insulin resistance linked to increased dementia risk and brain atrophy. However, the degree to which peripheral and cerebral glucose dysregulation are coupled remains unclear. To address this, we used ultra-high-field ¹H MRS to directly quantify fasting brain glucose concentrations in the posterior cingulate cortex of 47 healthy adults from across the lifespan, with concurrent structural MRI and fasting blood glucose measurements. We found that both fasting blood and brain glucose increase with age but follow distinct trajectories: peripheral glucose rises significantly by midlife (40-60 years) and then plateaus, whereas cerebral glucose remains stable until older age (60-80 years) before increasing. Furthermore, brain glucose, but not blood glucose, independently predicts gray matter loss and partially mediates age-related atrophy, with effects strongest in subcortical, GLUT4-expressing regions. Our results provide direct in vivo evidence that higher fasting brain glucose levels are associated with age-related gray matter loss, and suggest a delayed trajectory compared to peripheral glucose elevation, consistent with cerebral metabolic prioritization. Brain glucose measured by MRS represents a promising biomarker of metabolic dysfunction that may enable early detection of neuronal vulnerability and inform interventions targeting brain-specific glucose metabolism.