title: Amyloid-beta in Alzheimer disease: the null versus the alternate hypotheses.
abstract: For nearly 20 years, the primary focus for researchers studying Alzheimer disease has been centered on amyloid-beta, such that the amyloid cascade hypothesis has become the "null hypothesis." Indeed, amyloid-beta is, by the current definition of the disease, an obligate player in pathophysiology, is toxic to neurons in vitro, and, perhaps most compelling, is increased by all of the human genetic influences on the disease. Therefore, targeting amyloid-beta is the focus of considerable basic and therapeutic interest. However, an increasingly vocal group of investigators are arriving at an "alternate hypothesis" stating that amyloid-beta, while certainly involved in the disease, is not an initiating event but rather is secondary to other pathogenic events. Furthermore and perhaps most contrary to current thinking, the alternate hypothesis proposes that the role of amyloid-beta is not as a harbinger of death but rather a protective response to neuronal insult. To determine which hypothesis relates best to Alzheimer disease requires a broader view of disease pathogenesis and is discussed herein.
authors.affiliation: Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106, USA.
authors.forename: Hyoung-gon
authors.initials: HG
authors.lastname: Lee
authors.forename: Xiongwei
authors.initials: X
authors.lastname: Zhu
authors.forename: Rudy J
authors.initials: RJ
authors.lastname: Castellani
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nunomura
authors.forename: George
authors.initials: G
authors.lastname: Perry
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D017382:Reactive Oxygen Species