The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation

Several pathogenic Alzheimer's disease (AD) mutations have been described, all of which cause increased amyloid beta -protein (A beta) levels. Here we present studies of a pathogenic amyloid precursor protein (APP) mutation, located within the A beta sequence at codon 693 (E693G), that causes AD in a Swedish family. Carriers of this 'Arctic' mutation showed decreased A beta 42 and A beta 40 levels in plasma. Additionally, low levels of A beta 42 were detected in conditioned media from cells transfected with APP(E693G). Fibrillization studies demonstrated no difference in fibrillization rate, but A beta with the Arctic mutation formed protofibrils at a much higher rate and in larger quantities than wild-type (wt) A beta. The finding of increased protofibril formation and decreased A beta plasma levels in the Arctic AD may reflect an alternative pathogenic mechanism for AD involving rapid A beta protofibril formation leading to accelerated buildup of insoluble A beta intra- and/or extracellularly.