We investigated the cleavage of caspase-3, a marker of apoptosis, in the medial temporal lobe of older subjects with minimal cognitive deficits and low CERAD/intermediate Braak scores, that is, clinicopathological descriptors of early Alzheimer's disease (AD). The activation of caspase-3 was studied with immunoprecipitation-mass spectroscopy and immunocytochemistry, including colocalization with paired helical filaments in the neuropil and perikarya. We found that caspase-3 is activated in the parahippocampal gyrus in subjects with mild AD and that this event is silenced in more advanced illness. Caspase-3 immunoreactivity has a tangle-like appearance that coevolves with paired helical filament pathology within neurons. We propose that activation of apoptosis may occur very early in the medial temporal lobe in AD.