Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease

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 PSI (P < 0.0001), PS2(N1411) (P = 0.009), APP(K670N,M671L) (P < 0.0001), and APP(V7171) (one subject) mutations. Aβ ending at A1β42(43) was also significantly elevated in fibroblast media from subjects with PS1 (P < 0.0001) or PS2 (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.