To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and amyloid β-protein precursor (APP) mutations linked to familial Alzheimer's disease (FAD) increase the extracellular concentration of amyloid β–protein (Aβ) ending at Aβ42(43) in vivo, we performed a blinded comparison of plasma Aβ levels in carriers of these mutations and controls. Aβ1 –42(43) was elevated in plasma from subjects with FAD–linked PS1 (P < 0.0001), PS2_N141I(P = 0.009), APP_K670N,M671L(P < 0.0001), and APP_V717I (one subject) mutations. Aβ ending at Aβ42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or P52 (P = 0.03) mutations. These findings indicate that the FAD–linked mutations may all cause Alzheimer's disease by increasing the extracellular concentration of Aβ42(43), thereby fostering cerebral deposition of this highly amyloidogenic peptide.