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. Ann Neurol 2003;54:393–398