An inverse-Warburg effect and the origin of Alzheimer’s disease

Glycolysis and oxidative phosphorylation (OxPhos) are the two major mechanisms involved in brain energetics. In this article we propose that the sporadic forms of Alzheimer’s disease (AD) are driven by age-related damage to macromolecules and organelles which results in the following series of dynamic processes. (1) Metabolic alteration: Upregulation of OxPhos activity by dysfunctional neurons. (2) Natural selection: Competition for the limited energy substrates between neurons with normal OxPhos activity [Type (1)] and dysfunctional neurons with increased OxPhos [Type (2)]. (3) Propagation, due to the fact that Type (1) neurons are outcompeted for limited substrate by Type (2) neurons which, because of increased ROS production, eventually become dysfunctional and die. Otto Warburg, in his studies of the origin of cancer, discovered that most cancer cells are characterized by an increase in glycolytic activity—a property which confers a selective advantage in oncologic environments. Accordingly, we propose the term “inverse-Warburg effect” to describe increased OxPhos activity—a property which we propose confers a selective advantage in neuronal environments, and which we hypothesize to underlie the shift from normal to pathological aging and subsequent AD.