A review of over 2,000 cases of Creutzfeldt-Jakob disease and related disorders in the literature and our own files yielded 231 cases of dementia with early lower motor neuron signs. The clinical-pathological profiles of the 231 cases were distinctly different from those of cases of transmissible Creutzfeldt-Jakob disease: the patients had a longer illness, and their brains lacked the typical spongiform change. Brain tissue from 33 of these patients has been inoculated intracerebrally into nonhuman primates, but only 2 atypical cases transmitted a spongiform encephalopathy; 23 have been incubating from three to twelve years and can be considered negative transmission experiments. The findings suggest that most cases of dementia associated with early amyotrophy are more closely related to classic amyotrophic lateral sclerosis than to transmissible Creutzfeldt-Jakob disease and do not deserve the label of "amyotrophic Creutzfeldt-Jakob disease." When lower motor neuron involvement occurs in transmissible Creutzfeldt-Jakob disease, it is usually late and accompanied by signs of a more fulminant cerebral and cerebellar involvement.