Could Alzheimer’s Disease Be a Maladaptation of an Evolutionary Survival Pathway Mediated by Intracerebral Fructose and Uric acid Metabolism?

Abstract

An important aspect of survival is to assure enough food, water and oxygen. Here we describe a recently discovered response that favors survival in times of scarcity, and it is initiated by either ingestion or production of fructose. Unlike glucose which is a source for immediate energy needs, fructose metabolism results in an orchestrated response to encourage food and water intake, reduce resting metabolism, stimulate fat and glycogen accumulation, and induce insulin resistance as a means to reduce metabolism and preserve glucose supply for the brain. How this survival mechanism affects brain metabolism, which in the resting human amounts to 20 % of overall energy demand, is only beginning to be understood. Here we review and extend a previous hypothesis that this survival mechanism has a major role in the development of Alzheimer’s disease, and may account for many of the early features, including cerebral glucose hypometabolism, mitochondrial dysfunction, and neuroinflammation. We propose that the pathway can be engaged by multiple ways, including by diets high in sugar, high glycemic carbohydrates and salt. In summary, we propose that Alzheimer’s disease may be the consequence of a maladaptation to an evolutionary-based survival pathway, and what had served to enhance survival, acutely becomes injurious when engaged for extensive periods. While more studies are needed on the role of fructose metabolism and its metabolite, uric acid, in Alzheimer’s disease, we suggest that both dietary and pharmacologic trials to reduce fructose exposure or block fructose metabolism should be performed to determine if there is potential benefit in the prevention, management or treatment of this disease.