Although it is recognized that changes in protease activities may be involved in the etiology of pathological changes in the human brain, there have been few studies on normal and pathological protein catabolism. In the present study the activities of major cortical aminopeptidase and prolylendopeptidase were determined in frontal and medial temporal cortical samples of brains from patients with Alzheimer's disease (AD) and control patients matched for age. Prolylendopeptidase activity was reduced by 45-50% in the frontal and medial temporal cortex of AD patients as compared with controls, whereas major aminopeptidase activity was unaltered. The possibility that the changes in peptidase activities in AD are age-dependent was studied in postmortem neocortical samples from 18 AD patients who had died between 55 and 90 years of age. Prolylendopeptidase activity was lower in patients who died at a relatively early age than in patients who died at a relatively old age. This underscores the notion that, with respect to age, there may be heterogeneity in neurochemical changes in AD.