Skin fibroblasts from patients with Alzheimer's disease and from apparently normal control subjects were compared for their production of a cholinergic differentiating factor. The factor's activity was assayed by measuring the induction of choline acetyltransferase (CAT) activity in cultured sympathetic neurons. Culture medium conditioned by exposure to normal human fibroblasts induced substantial levels of CAT activity in sympathetic neurons, indicating that human fibroblasts produce a soluble factor that promotes cholinergic expression. In contrast, medium conditioned by Alzheimer fibroblasts induced only about one-third as much CAT activity, a highly significant reduction (p less than 0.01). These observations suggest that Alzheimer fibroblasts may be deficient in their secretion of a cholinergic factor and raise the possibility that the pathophysiology of the disease is related to a defect in the release of this factor. The fibroblast abnormalities suggest that Alzheimer's disease may be a systemic disease involving nonneuronal cells that are outside as well as within the brain.