An integrative multi-omics study reveals glutamine metabolism dysregulation connecting Alzheimer's disease and age-related macular degeneration

BackgroundAlzheimer's disease (AD) and age-related macular degeneration (AMD) are two common neurodegenerative diseases with many similar pathological features, but their shared metabolic characteristics have not been fully elucidated.ObjectiveThis study aims to explore the shared metabolic pathways between AD and AMD using an integrated multi-omics strategy.MethodsWe incorporated Mendelian randomization (MR), bulk and single-cell transcriptomics, and targeted metabolomics to investigate the metabolic links.ResultsThrough MR, we found elevated genetically inferred glutamine concentrations were correlated with a lower likelihood of AD but a higher likelihood of AMD. Using transcriptomic profiling, we detected 19 common differentially expressed genes associated with glutamine and glutamate metabolism, such as GLS. Analysis of single-cell RNA sequencing data revealed that GLS displays distinct cell-type expression patterns. Targeted metabolomic profiling in APP/PS1 mice at 5 months of age provided additional evidence for alterations in glutamine metabolism. The degree of metabolic changes in the eyes was higher than that in the cortex and hippocampus, and the prominent eyes may be an early indicator of neurodegenerative metabolic dysfunction.ConclusionsOverall, these findings suggest that glutamine metabolism disorders represent a convergent mechanism between AD and AMD. Our findings shed light on the overlapping metabolic pathways linking AD and AMD, underscoring the value of ocular biomarkers as promising tools for early disease detection.