Mild cognitive impairment (MCI), the earliest clinically detectable phase of the trajectory toward dementia and Alzheimer's disease (AD), led to the need for even earlier detection and prevention of AD. Although it is a clinical diagnosis, its underlying neuropathological findings are just being defined. MCI is best studied in longitudinally followed patients in centers that are experienced in dementing disorders. In this review of the few major clinical-pathological reports of longitudinally followed patients, it appears that most autopsied amnestic MCI (aMCI) patients are on a pathway toward AD. Neurofibrillary pathology in entorhinal cortex, hippocampus, and amygdala--not amyloid plaques--is the major substrate for aMCI and for memory decline. In addition, many MCI patients have other concomitant pathological alterations, the most common of which are strokes, but also include argyrophilic grains and Lewy bodies. These findings are not surprising because most MCI autopsied cases have been in the older (80 to 90 year) range where these findings are common. In early AD, the phase following MCI, the significant change is an increase in neurofibrillary tangles in the neocortex that correlates with an increase in Braak score and the observed clinical progression.