SECRETED AMYLOID BETA-PROTEIN SIMILAR TO THAT IN THE SENILE PLAQUES OF ALZHEIMERS-DISEASE IS INCREASED IN-VIVO BY THE PRESENILIN-1 AND PRESENILIN-2 AND APP MUTATIONS LINKED TO FAMILIAL ALZHEIMERS-DISEASE

To determine whether the presenilin 1 (PS1), presenilin 2 (PS2) and am yloid beta-protein precursor (APP) mutations linked to familial Alzhei mer's disease (FAD) increase the extracellular concentration of amyloi d beta-protein (A beta) ending at A beta 42(43) in vivo, we performed a blinded comparison of plasma A beta levels in carriers of these muta tions and controls. A beta 1-42(43) was elevated in plasma from subjec ts with FAD-linked PS1 (P < 0.0007), PS2(N141I) (P = 0.009), APP(K670N ,M671L) (P < 0.0001), and APP(Y717I) (one subject) mutations. A beta e nding at A beta 42(43) was also significantly elevated in fibroblast m edia from subjects with PS1 (P < 0.0001) or PS2 (P = 0.03) mutations. These findings indicate that the FAD-linked mutations may all cause Al zheimer's disease by increasing the extracellular concentration of A b eta 42(43), thereby fostering cerebral deposition of this highly amylo idogenic peptide.