Recent studies indicated that the formation of a major constituent of Alzheimer's disease (AD) senile plaques, called βA4‐peptide, does not result from normal processing of its precursor, amyloid precursor protein (APP). Since proteolytic cleavage of APP inside its βA4 sequence was found to be part of APP processing the formation of the βA4‐peptide seems to be prevented under normal conditions. We considered whether in AD one of the endogenous proteinase inhibitors might interfere with APP processing. After we had recently found that cultured human neuronal cells synthesize the most potent of the known human proteinase inhibitors, α‐2‐macroglobulin (α2M), upon stimulation with the inflammatory mediator interleukin‐6 (IL‐6) we now investigated whether α2M and IL‐6 could be detected in AD brains. Here we report that AD cortical senile plaques display strong α2M and IL‐6 immunoreactivity while no such immunoreactivity was found in age‐matched control brains. Strong perinuclear α2M immunoreactivity in hippocampal CAI neurons of Alzheimer's disease brains indicates that neuronal cells are the site of α2M synthesis in AD brains. We did not detect elevated IL‐6 or α2M levels in the cerebrospinal fluid of AD patients. Our data indicate that a sequence of immunological events which seem to be restricted to the local cortical environment is part of AD pathology.