Metabolic Dysfunction and Mitochondrial Failure in Alzheimer's Disease: Integrating Pathophysiology, Clinical Evidence and Emerging Interventions

Abstract

Alzheimer's disease (AD) is a gradual and irreversible decline in the brain's ability to function which is not only signified by amyloid-beta plaques and neurofibrillary tangles but also by and metabolic and mitochondrial changes that have a negative impact on the classical neuropathological hallmarks. It is becoming increasingly clear that the central roles in the process of synaptic dysfunction, neuronal death and cognitive decline are played by the brain's impaired glucose utilization, insulin resistance, lipid metabolism alterations, and energy homeostasis disruption. Mitochondrial dysfunctions in AD comprising of oxidative phosphorylation defects, ATP production decrease, reactive oxygen species generation over and above the normal level, poor mitochondrial dynamics, and vacuolar-type H+-ATPase-mediated cell death are the factors that further worsen the situation and hence speed up the process of neuronal death and eventually, disease progression. The metabolic and mitochondrial disturbances have a two-way relationship with amyloid-beta and tau pathology, neuroinflammation, and oxidative stress, thus creating a self-sustaining cycle of neurodegeneration. Besides, clinical and neuroimaging studies, fluorodeoxyglucose positron emission tomography, cerebrospinal fluid biomarkers, and peripheral metabolic profiling all support the notion that metabolic impairment is an early and clinically relevant feature of AD very convincingly. Thus, the attention of the scientific community has turned more and more toward the approaches that use the metabolic and mitochondrial pathways as their target. The new treatments are coming, including insulin sensitizers, ketogenic and Mediterranean diets, mitochondrial-targeted antioxidants, exercise, metabolic modulators, and new drugs, all aimed at bringing back equilibrium to bioenergetics and letting neurons live longer. In this review, we have considered the current mechanistic insights, clinical evidence, and therapeutic advances related to metabolic dysfunction and mitochondrial failure in AD together and their potential as early biomarkers and modifiable targets for disease prevention and treatment that are highlighted.