High-Throughput Metabolomics for Discovering Potential Biomarkers and Identifying Metabolic Mechanisms in Aging and Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is an aging-related neurodegenerative disease. We aimed to investigate the metabolic mechanisms of aging and AD and to identify potential biomarkers for the early screening of AD in a natural aging population. To analyze the plasma metabolites related to aging, we conducted an untargeted metabolomics analysis using ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry in a two-stage cross-sectional study. Spearman’s correlation analysis and random forest were applied to model the relationship between age and each metabolite. Moreover, a systematic review of metabolomics studies of AD in the PubMed, Cochrane and Embase databases were searched to extract the differential metabolites and altered pathways from original studies. Pathway enrichment analysis was conducted using Mummichog. In total, 669 metabolites were significantly altered with aging, and 12 pathways were enriched and correlated with aging. Three pathways (purine metabolism, arginine and proline metabolism, and the TCA cycle) were shared between aging and AD. Arginine and proline metabolism play a key role in the progression from healthy to mild cognitive impairment and to AD in the natural aging population. Three metabolites, 16-a-hydroxypregnenolone, stearic acid and PC[16:0/22:5(4Z,7Z,10Z,13Z,16Z)] were finally proposed as potential markers of AD in the natural aging population. The underlying mechanism shared between aging and AD and the potential biomarkers for AD diagnosis were proposed based on multistep comparative analysis.

Comparative Metabolomics Analysis Reveals Key Metabolic Mechanisms and Protein Biomarkers in Alzheimer’s Disease

“…AD-related human metabolites were collected from one recent systematic review ( Xie et al, 2021 ), which summarized 67 AD or mild cognitive impairment (MCI) patient metabolic profiling studies. Among the 67 studies, the number of AD cases ranged from 7 to 1,356, the number of MCI cases ranged from 10 to 356, and the number of healthy controls ranged from 7 to 23,882.…”

“…However, based on the complexity of the metabolites, different tissue distributions, different detection techniques, different populations and species can systemic abnormalities in metabolomic profiles. In this study, to compare AD-specific metabolomics alterations between AD animal models and human patients, we integrate multiple metabolic profiles from AD patients ( Xie et al, 2021 ) and mouse models. Significant metabolic pathways and metabolites are identified in AD.…”

Proline Metabolism in Neurological and Psychiatric Disorders

“…A high-throughput metabolomics study reported that proline metabolism plays a key role in the progression from healthy to mild cognitive impairment to AD in a natural aging population ( Xie et al, 2021 ). The disease-metabolite-pathway associations highlight the importance of proline in all three neurodegenerative diseases, including AD, PD, and ALS ( Kori et al, 2016 ).…”

Clinical Insights into Mitochondrial Neurodevelopmental and Neurodegenerative Disorders: Their Biosignatures from Mass Spectrometry-Based Metabolomics

“…In the case of Alzheimer's disease (AD), aging is the major risk factor with a doubling rate of incidence every five years after the age of 60 [171]. AD and aging also share several common metabolic changes in key metabolic pathways, such as the TCA cycle, the arginine biosynthesis pathway, the proline metabolic pathway and purine metabolism [172].…”