Mean age of onset in familial Alzheimer's disease is determined by amyloid beta 42

More than 130 known mutations in the presenilin-1 (PS1) gene result in familial Alzheimer's disease (FAD) with a mutation specific age of disease onset. These mutations increase amyloid beta 42 (Aβ42) levels, and this increase has been validated in recent years as one pathogenic factor in FAD. However, further malfunctions of mutant presenilin-1 are discussed as well. In order to assess the weight of Aβ42 regarding the pathogenesis of FAD, we expressed mutant forms of PS1 (30-65 years onset age) in COS-7 cells and analyzed amyloid beta levels by a novel ELISA. We found a strong correlation (r = 0.98; p < 0.001) between the Aβ40/42-ratio and mean age of disease onset indicating a substantial extent of Aβ42 contribution to FAD pathology. Our data strongly suggest that Aβ42 is the decisive factor for age of onset in FAD.