Sex Differences in the Association of Cerebral Blood Flow and Glucose Metabolism in Normative Aging

The coupling between cerebral blood flow (CBF) and glucose metabolism (CMR_GLC) is critical for maintaining brain function. However, sex differences in this relationship remain poorly understood, despite the heightened risk of cognitive decline from metabolic and vascular alterations in older women. Here, we address this gap by examining CBF-CMR_GLC associations in 79 younger and older females and males using simultaneous MR/PET imaging and cognitive testing. Older adults exhibited weakened correlations between CBF and CMR_GLC across functional networks. Sex moderated this decline, with older females showing significant negative CBF-CMR_GLC associations, a pattern absent in older males and younger females. Individuals with stronger CBF-CMR_GLC coupling performed better cognitively. Functional network parcellations (versus anatomical) better captured these sex- and age-specific effects. Our results support the idea that brain function depends not only on absolute metabolic substrate availability but on their coordinated use across functional networks. We conclude that the reduced cognitive performance of older adults is attributable to a loss of synchronized vascular and metabolic dynamics in functional networks. Other factors moderate this association, including sex and cardiometabolic health. Across older females, there are strong, negative network CBF-CMR_GLC correlations, possibly reflecting a compensatory response in the face of attenuated rates of blood flow and glucose metabolism. The coupling of CBF and CMR_GLC may serve as a biomarker for brain health and neurological conditions.