ALZHEIMER'S disease is characterized by the extracellular deposition in the brain and its blood vessels of insoluble aggregates of the amyloid β-peptide (Aβ), a fragment, of about 40 amino acids in length, of the integral membrane protein β-amyloid precursor protein (β-APP)¹. The mechanism of extracellular accumulation of αβ in brain is unknown and no simple in vitro or in vivo model systems that produce extracellular Aβ have been described. We report here the unexpected identification of the 4K (M_r 4,000) Aβ and a truncated form of Aβ (∼3K) in media from cultures of primary cells and untransfected and β-APP-transfected cell lines grown under normal conditions. These peptides were immunoprecipitated readily from culture medium by Aβ-specific antibodies and their identities confirmed by sequencing. The con-cept that pathological processes are responsible for the production of Aβ must now be reassessed in light of the observation that Aβ is produced in soluble form in vitro and in vivo² during normal cellular metabolism. Further, these findings provide the basis for using simple cell culture systems to identify drugs that block the formation or release of Aβ, the primary protein constituent of the senile plaques of Alzheimer's disease.