TY - JOUR T1 - Amyloid-β in Alzheimer Disease: The Null versus the Alternate Hypotheses JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 823 LP - 829 DO - 10.1124/jpet.106.114009 VL - 321 IS - 3 AU - Hyoung-gon Lee AU - Xiongwei Zhu AU - Rudy J. Castellani AU - Akihiko Nunomura AU - George Perry AU - Mark A. Smith Y1 - 2007/06/01 UR - http://jpet.aspetjournals.org/content/321/3/823.abstract N2 - For nearly 20 years, the primary focus for researchers studying Alzheimer disease has been centered on amyloid-β, such that the amyloid cascade hypothesis has become the “null hypothesis.” Indeed, amyloid-β 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-β 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-β, 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-β 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. The American Society for Pharmacology and Experimental Therapeutics ER -