Evidence that A beta 42 plasma levels in presenilin-1 mutation carriers donot allow for prediction of their clinical phenotype

Mutations in the presenilin I (PSEN1) gene are an important cause of autoso mal dominant Alzheimer's disease (AD). Both in vitro and in vivo experiment s showed that PSEN1 mutations increase secretion of amyloid beta 42 (A beta 42), the longer and more fibrillogenic isoform of A beta. We measured secr eted 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, w ith a similar severe phenotype In terms of onset age (mean 35 years), durat ion of the disease (mean 6.5 years), and pathology. Both families segregate a different missense mutation in PSEN1 located in different parts of the p rotein: [143T in family AD/A and G384A in family AD/B. A significant increa se 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 PS EN1 mutations on A beta 42 secretion was also detected in conditioned mediu m of stably transfected HEK293 cells. Both mutations increased A beta 42 se cretion significantly; however, the increase was highest for G384A (5.5-fol d over wild-type PSEN1), the largest effect observed for missense PSEN1 mut ations to date. Although the A beta 42 concentrations measured in vivo and in vitro did not correlate with onset age, a positive correlation was obtai ned with age in the presymptomatic mutation carriers and a negative correla tion 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.