Application of Metabolomics in Alzheimer’s Disease

Abstract

Progress toward the development of efficacious therapies for Alzheimer’s disease (AD) is halted by a lack of understanding early underlying pathological mechanisms. Systems biology encompasses several techniques including genomics, epigenomics, transcriptomics, proteomics, and metabolomics. Metabolomics is the newest omics platform that offers great potential for the diagnosis and prognosis of neurodegenerative diseases as an individual’s metabolome reflects alterations in genetic, transcript, and protein profiles and influences from the environment. Advancements in the field of metabolomics have demonstrated the complexity of dynamic changes associated with AD progression underscoring challenges with the development of efficacious therapeutic interventions. Defining systems-level alterations in AD could provide insights into disease mechanisms, reveal sex-specific changes, advance the development of biomarker panels, and aid in monitoring therapeutic efficacy, which should advance individualized medicine. Since metabolic pathways are largely conserved between species, metabolomics could improve the translation of preclinical research conducted in animal models of AD into humans. A summary of recent developments in the application of metabolomics to advance the AD field is provided below.

Altered Bile Acid Profile in Mild Cognitive Impairment and Alzheimer’s Disease: Relationship to Neuroimaging and CSF Biomarkers

“…Several metabolic perturbations have been noted in Alzheimer's disease (AD) including failures associated with cholesterol metabolism [1][2][3] which has been associated with AD in multiple lines of research including physiological and epidemiological studies. [3][4][5] Cholesterol is synthesized in liver and its clearance involves bile acid (BA) production by gut microbiome and human co-metabolism.…”

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

“…According to the authors, AD is characterized by a combination of several interrelating pathological events that include bio-energetic, metabolic, neurovascular, and inflammatory processes. Other researchers point out the fact that brain hypo-metabolism occurs decades prior to the clinical manifestation, which suggests that metabolic dysfunction is an important contributing factor to AD (Wilkins and Trushina 2018). Until now, the lack of comprehensive analysis and particular methodology has limited the development of AD diagnosis and therapy.…”

Alzheimer's disease mechanisms in peripheral cells: Promises and challenges

“…These findings suggest that altered mitochondrial dynamics and function represent a common nexus between familial and sporadic cases of the disease where human skin fibroblasts share mitochondrial defects observed in the AD brain [45]. Changes in mitochondrial function in AD fibroblasts also recapitulate metabolic alterations in energy pathways that we and others identified in the CSF and plasma from patients with MCI and AD [32,51,56]. These findings support the hypothesis that impairment of bioenergetics, mitochondrial dynamics and function, and cell metabolism occur throughout the body and contribute to the pathophysiology of AD providing a rationale for the analysis of mitochondrial bioenergetics in peripheral tissues as a promising strategy to develop new diagnostic methods for AD [33].…”