Normal processing of the amyloid beta protein precursor (beta APP) results in secretion of a soluble 4-kilodalton protein essentially identical to the amyloid beta protein (A beta) that forms insoluble fibrillar deposits in Alzheimer’s disease. Human neuroblastoma (M17) cells transfected with constructs expressing wild-type beta APP or the beta APP(717) mutants linked to familial Alzheimer’s disease were compared by (i) isolation of metabolically labeled 4-kilodalton A beta from conditioned medium, digestion with cyanogen bromide, and analysis of the carboxyl-terminal peptides released, or (ii) analysis of the A beta in conditioned medium with sandwich enzyme-linked immunosorbent assays that discriminate Ap(1-40) from the longer AP(1-42). Both methods demonstrated that the 4-kilodalton Ap released from wild-type beta APP is primarily but not exclusively AP(1-40). The beta APP(717) mutations, which are located th ree residues carboxyl to A beta(43), consistently caused a 1.5- to 1.9-fold increase in the percentage of longer A beta generated. Long A beta (for example, A beta(1-42)) forms insoluble amyloid fibrils more rapidly than Ap(1-40). Thus, the beta APP(717) mutants may cause Alzheimer’s disease because they secrete increased amounts of long A beta, thereby fostering amyloid deposition.