title: Linking Abeta and tau in late-onset Alzheimer's disease: a dual pathway hypothesis.
abstract: Alzheimer's disease is characterized by abnormal elevation of Abeta peptide and abnormal hyperphosphorylation of the tau protein. The "amyloid hypothesis," which is based on molecular defects observed in autosomal-dominant early-onset Alzheimer's disease (EOAD), suggests a serial model of causality, whereby elevation of Abeta drives other disease features including tau hyperphosphorylation. Here, we review recent evidence from drug trials, genetic studies, and experimental work in animal models that suggests that an alternative model might exist in late-onset AD (LOAD), the complex and more common form of the disease. Specifically, we hypothesize a "dual pathway" model of causality, whereby Abeta and tau can be linked by separate mechanisms driven by a common upstream driver. This model may account for the results of recent drug trials and, if confirmed, may guide future drug development.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Department of Neurology, Columbia University College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. sas68@columbia.edu
authors.forename: Scott A
authors.initials: SA
authors.lastname: Small
authors.forename: Karen
authors.initials: K
authors.lastname: Duff
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008959:Models, Neurological; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D016875:tau Proteins