Among brain regions affected in Alzheimer's disease (AD), the posterior cingulate shows the earliest and largest decrement in energy metabolism. Positron emission tomography (PET) studies have shown that these decrements appear before the onset of memory deficits or other symptoms in persons at genetic risk for AD. This study compares in vivo imaging results and in situ postmortem analyses by examining the posterior cingulate (area 23) in 15 AD patients and 13 age-matched nondemented controls using quantitative cytochrome oxidase histochemistry as an intracellular measure of oxidative energy metabolic capacity. Each of the six layers of the posterior cingulate demonstrated a decline in cytochrome oxidase activity in AD relative to controls, whereas adjacent motor cortex showed no significant differences. This decrement did not appear to be mainly secondary to nonspecific decrement in mitochondrial enzymes, oxidative stress, cell loss, or histopathology. The cytochrome oxidase decrement was most severe in the superficial layer I (−39%), which demonstrated a correlation to disease duration. Covariance analyses suggest that superficial laminas undergo a functional uncoupling from the deeper layers of posterior cingulate cortex in AD, whereas no such effects are found in motor cortex or controls. These findings expand on previous results from PET studies by illuminating the layer-specific cytochrome oxidase contributions to energy hypometabolism. The findings suggest a decrement of cytochrome oxidase in posterior cingulate cortex, with progressive reduction within the superficial laminas linked to disease duration. Such decrement could contribute to some of the behavioral symptoms displayed by AD patients. This decrement appeared greater in women.