Mean age-of-onset of familial Alzheimer disease caused by presenilin mutations correlates with both increased Aβ42 and decreased Aβ40

The varied ways in which mutations in presenilins (PSEN1 and PSEN2) affect amyloid beta precursor protein (APP) processing in causing early,onset familial Alzheimer disease (FAD) are complex and not yet properly understood. Nonetheless, one useful diagnostic marker is an increased ratio of A beta 42 to A beta 40 (A beta 42/A beta 40) in patients' brain and biological fluids as well as in transgenic mice and cells. We studied A beta and APP processing for a set of nine clinical PSEN mutations on a novel and highly reproducible enzyme-linked immunosorbent assay (ELISA)-based in vitro method and also sought correlation with brain A beta analyzed by image densitometry and mass spectrometry. All mutations significantly increased A beta 42/A beta 40 in vitro by significantly decreasing A beta 40 with accumulation of APP C,terminal fragments, a sign of decreased PSEN activity. A significant increase in absolute levels of A beta 42 was observed for only half of the mutations tested. We also showed that age-of-onset of PSEN1-linked FAD correlated inversely with A beta 42/A beta 40 (r = -0.89; P = 0.001) and absolute levels of A beta 42 (r = -0.83; P = 0.006), but directly with A beta 40 levels (r = 0.69; P = 0.035). These changes also partly correlated with brain A beta 42 and A beta 40 levels. Together, our data suggested that A040 might be protective by perhaps sequestering the more toxic A beta 42 and facilitating its clearance. Also, the in vitro method we describe here is a valid tool for assaying the pathogenic potential of clinical PSEN mutations in a molecular diagnostic setting. Hum Mutat 27(7), 686-695, 2006. Published 2006 Wiley-Liss, Inc.(dagger).