Oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) are markers of oxygen homeostasis that may offer insights into abnormal changes in brain aging. The present study cross-sectionally related OEF and CMRO2 to cognitive performance and structural neuroimaging variables among older adults (n=247, 74±7 years, 36% female) and tested whether apolipoprotein E (APOE)-ε4 status modified these associations. Main effects of OEF and CMRO2 were null (p-values>0.05), and OEF interactions with APOE-ε4 status on cognitive and structural imaging outcomes were null (p-values>0.07). However, CMRO2 interacted with APOE-ε4 status on language (p=0.002), executive function (p=0.03), visuospatial (p=0.005), and episodic memory performances (p=0.03), and on hippocampal volume (p=0.006) and inferior lateral ventricle volume (p=0.02). In stratified analyses, lower oxygen metabolism related to worse cognition and smaller grey matter volumes in APOE-ε4 carriers only, with significant effects on the domains of language (p=0.02) and episodic memory performance (p=0.03). Congruence across language and episodic memory results as well as hippocampal and inferior lateral ventricle volume findings suggests that APOE-ε4 may interact with cerebral oxygen metabolism early in the pathogenesis of Alzheimer’s disease and related neurodegeneration with meaningful clinical consequences.