The protein products of the Jun and Fos immediate early gene (IEG) families are cooperative transcriptional regulatory factors implicated in regulating the expression of many genes. The levels of a variety of proteins such as the amyloid precursor protein and basic fibroblast growth factor are altered in Alzheimer's disease (AD), thus the events regulating these changes are of interest. Both of these genes contain an activator protein-1 consensus sequence which may be responsive to regulation by immediate early genes. In order to evaluate the potential involvement of IEGs in AD pathology, we have examined Jun- and Fos-related protein immunoreactivity in control and AD brain. Specifically, we investigated the correspondence of immunoreactivity for Jun and Fos proteins with immunoreactivity for paired helical filament-1 (PHF-1), a marker for neurofibrillary tangles which recognizes abnormally phosphorylated tau, glial fibrillary acidic protein (GFAP), and thioflavine staining in double-labeling experiments. An intensification of both Jun and Fos immunoreactivity was observed in AD cases; in addition, both Jun and Fos immunoreactivity were colocalized with PHF-1 in some neurons in AD brain. Jun and Fos immunoreactivity were also colocalized with GFAP-positive astrocytes distributed in the cortex of AD and control cases, and surrounding thioflavine-stained plaques in AD brain. These observations suggest that members of the Jun and Fos IEG families may play a role in AD pathology.