Hypothalamic-pituitary-adrenal dysregulation is proposed as a risk factor for Alzheimer's disease (AD). This study assessed cross-sectional relationships between cortisol and neuroimaging biomarkers of brain structure and glucose metabolism across the AD spectrum. Participants with normal cognition, mild cognitive impairment, and AD were selected from the Alzheimer's Disease Neuroimaging Initiative databank, based on baseline measures of plasma cortisol, gray matter volume (n = 556), and cerebral glucose metabolism (n = 288). Relationships between plasma cortisol and the neuroimaging biomarkers were assessed. Across the entire cohort, higher plasma cortisol levels were associated with lower glucose metabolism in lateral and medial parietal regions. Higher plasma cortisol was also related to lower gray matter volume in temporal-parietal-occipital regions and in the hippocampus. There were no significant group differences in these relationships with adjustment for covariates. Our results demonstrate that hypothalamic-pituitary-adrenal axis activation is related to glucose hypometabolism within posterior cortical regions vulnerable to AD pathology. This regional pattern appears to be distinct from cortisol-related associations with brain structure. Future studies should delineate pathophysiological mechanisms underlying these effects.