Evidence that Aβ42 plasma levels in presenilin-1 mutation carriers do not allow for prediction of their clinical phenotype

Mutations in the presenilin I (PSEN1) gene are an important cause of autosomal dominant Alzheimer's disease (AD). Both in vitro and in vivo experiments showed that PSEN1 mutations increase secretion of amyloid beta 42 (A beta 42), the longer and more fibrillogenic isoform of A beta. We measured secreted A beta 42 in plasma of patients, presymptomatic mutation carriers, and escapees of two extended Belgian early-onset AD families, AD/A and AD/B, with a similar severe phenotype In terms of onset age (mean 35 years), duration of the disease (mean 6.5 years), and pathology. Both families segregate a different missense mutation in PSEN1 located in different parts of the protein: [143T in family AD/A and G384A in family AD/B. A significant increase in A beta 42 concentrations was observed in plasma of mutation carriers in family AD/B, but not in family AD/A. A differential effect of the two PSEN1 mutations on A beta 42 secretion was also detected in conditioned medium of stably transfected HEK293 cells. Both mutations increased A beta 42 secretion significantly; however, the increase was highest for G384A (5.5-fold over wild-type PSEN1), the largest effect observed for missense PSEN1 mutations to date. Although the A beta 42 concentrations measured in vivo and in vitro did not correlate with onset age, a positive correlation was obtained with age in the presymptomatic mutation carriers and a negative correlation with duration of disease in the patients. Our data obtained for PSEN1 mutation carriers suggest that measuring A beta 42 concentrations in plasma will be informative as a diagnostic marker in a limited number of cases. (C) 1999 Academic Press.