title: Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect.
abstract: Epidemiological and biochemical studies show that the sporadic forms of Alzheimer's disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events-mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.
authors: Department of Organismic and Evolutionary Biology, Harvard University Cambridge, MA, USA ; Max Planck Institute for Molecular Genetics Berlin, Germany.
authors: Lloyd A
authors: LA
authors: Demetrius
authors: Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology Thuwal, Saudi Arabia ; Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne Lausanne, Switzerland.
authors: Pierre J
authors: PJ
authors: Magistretti
authors: Laboratory of Neuroenergetics, Department of Physiology, University of Lausanne Lausanne, Switzerland.
authors: Luc
authors: L
authors: Pellerin
keywords: age-related disease; inverse cancer comorbidity; metabolic alteration; mitochondrial dysregulation; the Inverse Warburg effect
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