title: Mean age of onset in familial Alzheimer's disease is determined by amyloid beta 42.
abstract: 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 (A beta42) 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 A beta42 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 A beta40/42-ratio and mean age of disease onset indicating a substantial extent of A beta42 contribution to FAD pathology. Our data strongly suggest that A beta42 is the decisive factor for age of onset in FAD.
authors.affiliation: Center for Molecular Biology Heidelberg (ZMBH), Im Neuenheimer Feld 282, 69120 Heidelberg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Duering
authors.forename: Marcus O W
authors.initials: MO
authors.lastname: Grimm
authors.forename: Heike S
authors.initials: HS
authors.lastname: Grimm
authors.forename: Johannes
authors.initials: J
authors.lastname: Schröder
authors.forename: Tobias
authors.initials: T
authors.lastname: Hartmann
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000375:Aging / Q000235:genetics* / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism*; D053764:Presenilin-1; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42)