The histologically apparent polymorphism of plaques containing β-amyloid in Alzheimer's disease is thought to represent different stages in plaque evolution, β-amyloid-immunopositive plaques were classified according to the pattern of β-amyloid distribution (diffuse vs dense-core) and the presence or absence of dystrophic β-amyloid precursor protein-immunopositive (β-APP⁺) neurites (neuritic vs non-neuritic). The potential contribution of microglia-derived interleukin-1 (IL-1), an immune response cytokine that induces synthesis and processing of β-APP, to the possible sequential development of these plaque types was examined through determination of the number of IL-1α⁺ microglia associated with each of four identified plaque types. Diffuse non-neuritic plaques had the least dense and most widely dispersed β-amyloid, did not exhibit β-APP⁺ dystrophic neurites, but most (78%) contained activated IL-1α⁺ microglia (2 ± 0.2/plaque; mean ± SEM). Diffuse neuritic plaques had more dense, but still widely dispersed β-amyloid, displayed a profusion of β-APP⁺ dystrophic neurites, and had the greatest numbers of associated activated IL-1±⁺ microglia (7 ± 0.8/plaque). Dense-core neuritic plaques had both compact and diffuse β-amyloid and had fewer IL-1±⁺ microglia (4 ± 0.4/plaque). Dense-core, non-neuritic plaques had compact β-amyloid, lacked associated diffuse β-amyloid, and were devoid of both IL-1α⁺ microglia and β-APP⁺ dystrophic neurites. These results suggest an important immunological component in the evolution of amyloid-containing plaques in Alzheimer's disease and further suggest that IL-1-expressing cells are necessary to initiate dystrophic neurite formation in diffuse β-amyloid deposits. Our data indicate that activation of microglia with expression of IL-1 in Alzheimer's disease is required to drive the metamorphosis of diffuse non-neuritic β-amyloid deposits to the characteristic and diagnostic neuritic plaques of Alzheimer's disease.