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.
Highlights
Alzheimer’s disease (AD) is an aging-related neurodegenerative disease characterized by senile plaques caused by amyloid beta (Aβ) and neurofibrillary tangles containing hyperphosphorylated tau-protein
We aimed to explore similar metabolomic signatures among AD, mild cognitive impairment (MCI) and aging, which could help explain the high incidence of AD in older populations and suggest novel markers to identify the earliest phase of AD in the natural aging population
The key finding of this study is the systematic comparison of the metabolic mechanisms of AD, MCI, and aging
Summary
Alzheimer’s disease (AD) is an aging-related neurodegenerative disease characterized by senile plaques caused by amyloid beta (Aβ) and neurofibrillary tangles containing hyperphosphorylated tau-protein. Current estimates suggest that 44 million people live with dementia worldwide. This figure is predicted to more than triple by 2050 as the population ages; at this time, the annual cost of dementia in the United States alone may exceed US$600 billion (Lane et al, 2017; Nichols et al, 2019). Mild cognitive impairment (MCI, “amnestic MCI” is seen as a prodromal stage of Alzheimer’s disease) represents the clinically diagnosed predementia stage. The current diagnosis is based on clinical symptoms of AD combined with pathological alterations, such as a decrease of cerebrospinal fluid Aβ42 or an increase in p-tau or t-tau protein, which may not identify a substantial number of asymptomatic individuals who will develop AD later. It is urgent to investigate the physiology of AD and/or MCI and detect early biomarkers to improve the quality of life of those affected by this disease
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