Cytochrome c has a well-established role in electron transfer and as a mediator of apoptotic cell death. The cortical and intracellular localisation of cytochrome c immunoreactivity was examined in Alzheimer's disease and control cases. No differences in the cortical labelling pattern or the density of cytochrome c-positive cells in neocortical layer V were present between control and Alzheimer's disease cases. Punctate cytochrome c labelling was present in a subset of neocortical neurons, including clusters of intensely labelled pyramidal neurons that were not specifically associated with beta-amyloid plaques. With respect to Alzheimer's disease associated pathology, only 6.7 +/- 1.4% of neurons showing neurofibrillary tangle formation demonstrated punctate cytochrome c immunoreactivity. These results suggest that cytochrome c may label a subset of pyramidal neurons that is susceptible, yet relatively resistant, to Alzheimer's disease pathology. A low percentage of neurofilament triplet protein medium, tau and chromogranin A labelled dystrophic neurites were also cytochrome c-positive. There was also a trend towards an increase in the percentage of cytochrome c immunoreactive dystrophic neurites in pathologically aged control cases compared to Alzheimer's disease cases, suggesting that cytochrome c may be an early and transient epitope within dystrophic neurites. In contrast to the punctate cytochrome c labelling observed in cortical cells, cytoplasmic cytochrome c labelling was observed within dystrophic neurites. Although cytochrome c release is indicative of the activation of the intrinsic apoptotic pathway, cytoplasmic cytochrome c may also indicate mitochondrial damage or dysfunction.