Increased synthesis and release of S100 beta protein from activated astrocytes has been implicated in the overgrowth of dystrophic neurites in neuritic plaques in Alzheimer disease (AD). To evaluate the quantitative relationships between tissues levels of S100 beta and the numbers of neuritic plaques in AD patients, we counted neuritic plaques, by Tau-2 immunoreactive (Tau-2+) labeling, in tissue sections of hippocampus and adjacent temporal cortex and measured the levels of S100 beta protein, by Western immunoblot labeling, in samples of analogous regions from contralateral hemisphere of the same patients. In AD, tissue levels of S100 beta (two- to fivefold that of controls) were significantly correlated with the number of Tau-2+ plaques (R = 0.82, P < .01). Dual-label immunohistochemical analysis showed that most S100 beta+ cells were activated GFAP+ astrocytes. These results were substantiated by a significant correlation between S100 beta and GFAP tissue levels (R = 0.81, P < .05). Many of the S100 beta+ astrocytes were clustered around and within Tau-2+ plaques. Indeed, no Tau-2+ plaques were found without associated activated S100 beta+ astrocytes. Our findings provide further evidence of a role for S100 beta protein in dysregulation of neurons that leads to apparently nonsensical growth of imperfect neurites in AD, a potential key element in early stages of neuritic plaque pathogenesis.