Shift in brain metabolism in late onset Alzheimer’s disease: Implications for biomarkers and therapeutic interventions

Abstract

Alzheimer’s is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised mitochondrial bioenergetics lead to over-production of and mitochondrial accumulation of β-amyloid, which is coupled with oxidative stress. Collectively, this results in a shift in brain metabolic profile from glucose-driven bioenergetics towards a compensatory, but less efficient, ketogenic pathway. We propose that the compensatory shift from a primarily aerobic glycolysis pathway to a ketogenic/fatty acid β-oxidation pathway eventually leads to white matter degeneration. The essential role of mitochondrial bioenergetics and the unique trajectory of compensatory metabolic adaptations in brain enable a bioenergetic-centric strategy for development of biomarkers. From a therapeutic perspective, this trajectory of alterations in brain metabolic capacity enables disease-stage specific strategies to target brain metabolism for disease prevention and treatment. A combination of nutraceutical and pharmaceutical interventions that enhance glucose-driven metabolic activity and potentiate mitochondrial bioenergetic function could prevent the antecedent decline in brain glucose metabolism, promote healthy aging and prevent AD. Alternatively, during the prodromal incipient phase of AD, sustained activation of ketogenic metabolic pathways coupled with supplementation of the alternative fuel source, ketone bodies, could sustain mitochondrial bioenergetic function to prevent or delay further progression of the disease.