title: Preventing Alzheimer's disease by means of natural selection.
abstract: The amyloid cascade model for the origin of sporadic forms of Alzheimer's disease (AD) posits that the imbalance in the production and clearance of beta-amyloid is a necessary condition for the disease. A competing theory called the entropic selection hypothesis asserts that the primary cause of sporadic AD is age-induced mitochondrial dysregulation and the following cascade of events: (i) metabolic reprogramming—the upregulation of oxidative phosphorylation in compensation for insufficient energy production in neurons, (ii) natural selection—competition between intact and reprogrammed neurons for energy substrates and (iii) propagation—the spread of the disease due to the selective advantage of neurons with upregulated metabolism. Experimental studies to evaluate the predictions of the amyloid cascade model are being continually retuned to accommodate conflicts of the predictions with empirical data. Clinical trials of treatments for AD based on anti-amyloid therapy have been unsuccessful. We contend that these anomalies and failures stem from a fundamental deficit of the amyloid hypothesis: the model derives from a nuclear-genomic perspective of sporadic AD and discounts the bioenergetic processes that characterize the progression of most age-related disorders. In this article, we review the anomalies of the amyloid model and the theoretical and empirical support for the entropic selection theory. We also discuss the new therapeutic strategies based on natural selection which the model proposes.
authors.forename: Lloyd A
authors.initials: LA
authors.lastname: Demetrius
authors.forename: Jane A
authors.initials: JA
authors.lastname: Driver
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000235:genetics* / Q000517:prevention & control*; D000682:Amyloid / Q000235:genetics / Q000502:physiology; D000818:Animals; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D008959:Models, Neurological; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D012641:Selection, Genetic; D013269:Stochastic Processes; D013816:Thermodynamics
chemical_list: D000682:Amyloid