A beta (beta/A4) is the major constituent of brain amyloid in Alzheimer's disease (AD), Down's syndrome (DS) and normal aged persons. This protein is presumably derived by normal proteolysis from a precursor protein (APP). In this study, C-terminal fragments of APP in a Tris/Triton soluble fraction were partially purified from DS brain by heparin-affinity and reverse phase chromatography, and analyzed by N-terminal amino acid sequencing after SDS polyacrylamide gel electrophoresis and Western blotting. We found at least six different C-terminal fragments including those with the entire A beta region. These results suggest that secretory processing of APP is heterogeneous and generates amyloidogenic C-terminal fragments.