Alzheimer's disease (AD) is associated with a progressive loss of locus ceruleus neurons. These noradrenergic neurons receive a major afferent projection from epinephrine neurons in epinephrine cell groups in the brainstem. The epinephrine neurons have a specific enzymatic marker, phenylethanolamine N-methyltransferase (PNMT), which allows them to be identified chemically and immunohistochemically. We have previously reported a decrease in PNMT in brains of patients with AD. We now report that the decrease in PNMT activity in projections to the locus ceruleus is not due to the loss of epinephrine neurons, although up to 33% of these neurons are atrophic. The decrease in presynaptic PNMT does, however, correlate with the loss of postsynaptic locus ceruleus neurons in brains from AD patients. The percentage of degenerating neurons in the epinephrine nuclei also correlates significantly with the amount of loss of locus ceruleus neurons in AD. In addition, there is a 55% decrease in mitogen activity, a nonspecific measure of growth or maintenance factors, in dialysed locus ceruleus extracts from the AD patients compared to those from control subjects. The mitogen activity in the locus ceruleus was significantly correlated with PNMT activity and with the density of locus ceruleus neurons in all cases examined. These findings provide evidence for the hypothesis that retrograde degeneration is a mechanism of neuronal degeneration in AD and suggest that trophic factors may play a role in this process.