We report our ongoing work to characterize the molecular nature of neurofibrillary tangles (NFT). An epitope map of tau protein using monoclonal antibodies that crossreact with NFT reveals the presence of epitopes that span the entire tau molecule from the amino terminus to the carboxy terminus. Several antibodies that recognize tau protein including Alz50 do not recognize primary amino acid sequence but are directed either against a post-translational modification or a complex higher order structure. The importance of tau protein in the development of the pathology is underscored by the extent of the tau-reactive neuritic lesions. These dystrophic neurites or "curly fibers" extend well beyond the classical distributions of the senile plaques and NFT. Furthermore, the neuropil lesion is considerably more extensive than either the senile plaques or neurofibrillary tangles. One of the features of the dystrophy in Alzheimer's disease is widespread neuronal sprouting characteristic of dystrophic neurites and tangle-bearing cells.