Within the neurofibrillary tangles (NFTs) and dystrophic neurites (DNs) of Alzheimer's disease (AD), the cytoskeletal protein tau is abnormally hyperphosphorylated. In this study we evaluate the phosphorylation of specific residues on tau within different phases of the formation of NFTs. Two monoclonal antibodies, AT8 and PHF-1, were used to selectively recognize phosphorylated Ser-202 and Ser-396 of PHF-tau protein, respectively. We found that abnormal phosphorylation of tau appears to occur first at Ser-202 in DNs, then at Ser-202 in the soma and finally at Ser-396 in DNs and NFTs. These results suggest that abnormal phosphorylation at Ser-202 of PHF-tau in DNs represents one of the earliest neuropathological changes within the neurites of vulnerable neurons and may have a pivotal role in the initial pathogenesis of AD.