AUTHOR=Demetrius Lloyd A. , Magistretti Pierre J. , Pellerin Luc 

TITLE=Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect

JOURNAL=Frontiers in Physiology

VOLUME=Volume 5 - 2014

YEAR=2015

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2014.00522

DOI=10.3389/fphys.2014.00522

ISSN=1664-042X

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.