Normal processing of the amyloid β protein precursor (βAPP) results in secretion of a soluble 4-kilodalton protein essentially identical to the amyloid β protein (Aβ) that forms insoluble fibrillar deposits in Alzheimer's disease. Human neuroblastoma (M17) cells transfected with constructs expressing wild-type βAPP or the βAPP₇₁₇ mutants linked to familial Alzheimer's disease were compared by (i) isolation of metabolically labeled 4-kilodalton Aβ from conditioned medium, digestion with cyanogen bromide, and analysis of the carboxyl-terminal peptides released, or (ii) analysis of the Aβ in conditioned medium with sandwich enzyme-linked immunosorbent assays that discriminate Aβ_1-40 from the longer Aβ_1-42. Both methods demonstrated that the 4-kilodalton Aβ released from wild-type βAPP is primarily but not exclusively Aβ_1-40. The βAPP₇₁₇ mutations, which are located three residues carboxyl to Aβ₄₃, consistently caused a 1.5- to 1.9-fold increase in the percentage of longer Aβ generated. Long Aβ (for example, Aβ_1-42) forms insoluble amyloid fibrils more rapidly than Aβ_1-40. Thus, the βAPP₇₁₇ mutants may cause Alzheimer's disease because they secrete increased amounts of long Aβ, thereby fostering amyloid deposition.