back to Fifth International Conference

S. Younkin, D. Scheuner , X. Song , C. Eckman, M. Citron, N. Suzuki, T. Bird;, J. Hardy, M. Hutton, L. Lannfelt, E. Levy-Lahad, E. Peskind;, P. Poorkaj, G. Schellenberg, R. Tanzi, M. Viitanen, W. Wasco, and D. Selkoe;

Mayo Clinic Jacksonville, Jacksonville, FL, Case Western Reserve Univ., Cleveland, OH, Harvard Univ., Boston, MA, Takeda Chem. Ind., Ltd., Japan, VA Med. Ctr., Seattle, WA., Univ. So. Florida, Tampa, FL, Karolinska Inst., Sweden, Univ. Washington, Seattle WA

• Enter the seminar

To determine whether the extracellular concentration of Aß is affected by the Presenilin 1 (PS1) and Presenilin 2 (PS2) mutations recently linked to familial AD (FAD), we performed a blinded comparison in carriers and controls of the concentrations of Aß in plasma and in skin fibroblast conditioned medium. Overall, we made 15 comparative measurements of (AßX-42(43)/ ßAPP synthesis) in control fibroblasts and groups of fibroblasts with 4 different PS1 mutations. In each of these 15 comparisons, (AßX-42(43)/ ßAPP synthesis) in the respective FAD family exceeded that in the controls. Overall, there was a highly significant (p=0.0002) increase in (AßX-42(43)/ ßAPP synthesis) in the 26 carriers vs. the 30 controls. Separate analysis of fibroblasts with specific mutations showed that the PS1G209V, PS1M146V, and PS1A246E mutations each significantly increased (AßX-42(43)/ ßAPP synthesis) vs. the 30 controls, and there was a consistent increase in groups of PS1L286V fibroblasts vs. controls, that was significant in the largest experiment. We also observed some increase in (Aß1-40/ßAPP synthesis) in fibroblasts from carriers vs. controls, but this increase did not achieve significance and it was not nearly as pronounced or definite. To determine if the PS1 mutations increase plasma Aß, we performed blinded analyses of plasma from controls and subjects with 4 different PS1 mutations. Analysis of plasma samples showed that Aß1-42(43) in 9 carriers was highly significantly (p=0.00003) increased vs. 14 non-carriers. Consistent with the fibroblast results, plasma AßX-42 was also significantly (p=0.02) increased in the carriers vs. the non-carriers. Plasma Aß1-40 was only slightly and non-significantly elevated in carriers as compared to non-carriers. We analyzed one subject with the APPV717I mutation, In this subject, plasma Aß1-42(43) was selectively elevated to 1.5 times the mean control value (20% higher than any of the controls), whereas Aß1-40 fell in the mid-control range. Recently, we compared fibroblasts and plasma from PS2N141I mutation carriers and controls. In both plasma (p=0.01) and fibroblast medium (p=0.04), Aß1-42(43) concentration was significantly increased in carriers, but Aß1-40 was not consistently elevated. These results show that, like the FAD-linked APP mutations, the PS1/2 mutations significantly increase the extracellular concentration of the highly amyloidogenic Aß1-42(43) peptide, a peptide that deposits selectively in the senile plaques that are an early, invariant feature of all forms of AD. This provides strong evidence that all of the FAD-linked mutations cause AD by increasing the extracellular concentration of Aß1-42(43), thereby fostering amyloid deposition, and they support the hypothesis that cerebrocortical Aß deposition is an essential early element in the pathogenesis of all forms of AD.