The accumulation in brain of senile plaques containing beta-amyloid protein (A beta) is a defining feature of Alzheimer's disease. The amyloid precursor protein (APP)4 from which A beta is derived is subject to several genetic mutations which segregate with rare familial forms of the disease, resulting in early onset of dementia and plaque formation, suggesting that APP metabolism plays a causal role in the disease. Various cell types have been shown to release a soluble form of A beta, thus allowing for the in vitro study of A beta generation. We report here evidence that a substantial portion of the APP secreted by human mixed brain cell cultures, as well as that present in cerebrospinal fluid, is of a novel form cleaved precisely at the amino terminus of A beta, suggesting that a secretory pathway is involved in A beta genesis.