We examined the associations of postmortem neocortical immunoreactivities for microglia, astrocytes, Abeta and Tau with cognitive changes in clinically characterized subjects with pathological diagnoses (CERAD classification) of definite AD (9), possible AD (15) and age-matched controls (11). By measuring the fractional area (FA) of immunoreactivity, we found that Abeta deposits appear early in the pathogenesis of Abeta, but cannot account for cognitive decline. We found a significant increases in FA for microglia in possible AD cases (nondemented) compared to controls (P<0.05) and in FA for astrocytes in definite AD (demented) compared to possible AD (P<0.01). Tau immunoreactivity was observed only in the neuropil of definite AD cases (P<0.001). The significant increase in microglia between controls and AD possible cases suggests that activation of microglia occurs in the early pathogenesis of AD, whereas the significant association between astrocytic reaction and dementia, suggests that these cells play a role in the late stage of the disease, when dementia develops. Tau immunoreactivity appears as the strongest morphological correlate of dementia.