The mitochondrial hypothesis: Dysfunction, bioenergetic defects, and the metabolic link to Alzheimer's disease

Abstract

Alzheimer's disease (AD) features mitochondrial dysfunction and altered metabolism. Other pathologies could drive these changes, or alternatively these changes could drive other pathologies. In considering this question, it is worth noting that perturbed AD patient mitochondrial and metabolism dysfunction extend beyond the brain and to some extent define a systemic phenotype. It is difficult to attribute this systemic phenotype to brain beta-amyloid or tau proteins. Conversely, mitochondria increasingly appear to play a critical role in cell proteostasis, which suggests that mitochondrial dysfunction may promote protein aggregation. Mitochondrial and metabolism-related characteristics also define AD endophenotypes in cognitively normal middle-aged individuals, which suggests that mitochondrial and metabolism-related AD characteristics precede clinical decline. Genetic analyses increasingly implicate mitochondria and metabolism-relevant genes in AD risk. Collectively these factors suggest that mitochondria are more relevant to the causes of AD than its consequences, and support the view that a mitochondrial cascade features prominently in AD. This chapter reviews the case for mitochondrial and metabolism dysfunction in AD and the challenges of proving that a primary mitochondrial cascade is pertinent to the disease.

Keywords: Alzheimer's disease; Metabolism; Mitochondria; Mitochondrial DNA; Proteostasis.