Dystrophic neurites in senile plaque (SP) coronas and neuropil threads (NTs) massively accumulate in Alzheimer's disease (AD) cortex. Hence, they may contribute to the cognitive deficits in AD. However, the composition of these neuritic lesions is poorly understood, and it is not known if they derive from axons, dendrites or both. To gain insights into the composition and derivation of SP neurites and NTs in AD, we undertook an in situ epitope mapping study wherein we probed these lesions using 278 monoclonal antibodies specific for spatially distinct epitopes in each neurofilament (NF) subunit, or in microtubule-associated proteins, i.e., tau and microtubule-associated protein 2. The middle molecular weight NF subunit (NF-M) and tau were extensively represented in SP neurites, i.e., epitopes extending from the NH2 to COOH domains of NF-M and tau were present. In contrast, microtubule-associated protein 2 was not present in any SPs, and only epitopes in the core domain of the low (NF-L), and in the tail piece of the high molecular weight subunit were detected in SP neurites. SP cores never stained with these antibodies. NTs were similar to SP neurites in that they contained the same complement of tau epitopes, and were devoid of any microtubule-associated protein 2 immunoreactivity, but they were also distinct because they rarely contained any NF determinants. These antigenic dissimilarities between SP neurites and NTs suggest that NTs and SP neurites are distinctly separate lesions that reflect widespread disruption of the neuronal cytoskeleton in AD.