A New Perspective on Alzheimer’s Disease as a Brain Expression of a Complex Metabolic Disorder

Abstract

Listen

Translate article

ABSTRACT Alzheimer’s disease (AD) is an irredeemable chronic neurodegenerative disorder and the predominant cause of dementia. The disease progression is associated with the deposition of amyloid plaques and formation of neurofibrillary tangles in the brain, yet clinical dementia is the end and culminating stage of the enduring pathology. Recent evidence suggests that AD is characterized by distinctive abnormalities apparent on systemic, histological, macromolecular, and biochemical levels. Besides the well-described characteristic profuse neurofibrillary tangles, dystrophic neurites, and Aβ deposits, the AD pathology includes substantial neuronal loss, inflammation, extensive DNA damage, considerable mitochondrial malfunction, impaired energy metabolism, and chronic oxidative stress. Moreover, severe metabolic dysfunction leading to oxidative stress is a possible cause and hallmark of AD that is apparent decades before the disease manifestation. State-of-the-art metabolomics studies have proved that arginine and branched-chain amino acids metabolism disturbances accompany AD and contribute to its pathogenesis. Repetitive failures to find an efficient anti-amyloid or anti-Tau treatment, which would face the challenges of the complex AD pathology, led to the hypothesis that hyperphosphorylated Tau and deposited Aβ proteins are hallmarks, not the ultimate causes of AD. Accordingly, the modern scientific vision of AD etiology and pathogenesis must reach beyond the hallmarks and look for alternative strategies and areas of research.