Alzheimer's disease (AD) causes progressive deterioration of cognition and behavior. Memory dysfunction is the hallmark, but there are also changes in behavior, emotion and autonomic functions, which cannot be explained simply as a consequence of memory impairment. These observations suggest that the natural disease process of AD involves not only memory-related neural structures, but also specific neural systems related to other behaviors, emotion and autonomic functions. Since recent evidence has indicated a primary role for ventromedial frontal (VMF) cortex in such functions, we examined laminar distribution of neurofibrillary tangles and Alz 50 immunoreactive neurons in subdivisions of VMF cortex in 20 AD patients and seven age-matched controls. The densities of pathological changes were: (i) highest in the posteromedial mesocortical regions, particularly Brodmann's area 25 (A25), posterior orbitofrontal cortex (POF) and anterior insula (AI); (ii) of comparable severity between posteromedial mesocortical regions and most temporal cortices, excluding only the entorhinal cortex and temporal pole; and (iii) located predominantly in layer III and especially layer V. Further analysis demonstrated selective pathology in layer V of A25, POF and AI that would disrupt direct cortico-autonomic projections. This is the first study to detail severe AD pathology in these autonomic-related cortices, which could contribute to the behavioral changes, emotional disturbance and autonomic dysregulation that often accompany AD.