We studied axonal damage in Alzheimer's disease frontal cortex and hippocampus with a novel monoclonal antibody (SMI 312) against phosphorylated neurofilaments. This antibody immunolabeled, with great detail, the neuropil axonal network. In aged normal cases only a few pyramidal cell perikarya were immunostained. In Alzheimer's disease there was a two- to four-fold increase in neuronal SMI 312 immunolabeling, and neuropil neuritic processes were severely disrupted. Double-immunolabeling analysis showed that 88% of SMI 312-immunolabeled abnormal neuritic clusters were associated with amyloid, whereas the remaining 12% were not. Serial section analysis and 3-D reconstructions suggested that dystrophic neurites of classical plaques were derived from long axons. These abnormal neurites were also growth-associated protein 43 positive and occasionally tau positive. The present study supports the contention that a subpopulation of aberrantly sprouting axons in the neuritic plaque is derived from cortico-cortico fibers. This disruption of the neocortical association fibers and neuritic microcircuitry could underlie the cognitive impairment of Alzheimer's disease.