RESUMEN
Introduction: Alzheimer's disease (AD) is a complex and progressive neurodegenerative disorder that primarily affects older individuals. N7-methylguanosine (m7G) is a common RNA chemical modification that impacts the development of numerous diseases. Thus, our work investigated m7G-related AD subtypes and established a predictive model. Methods: The datasets for AD patients, including GSE33000 and GSE44770, were obtained from the Gene Expression Omnibus (GEO) database, which were derived from the prefrontal cortex of the brain. We performed differential analysis of m7G regulators and examined the immune signatures differences between AD and matched-normal samples. Consensus clustering was employed to identify AD subtypes based on m7G-related differentially expressed genes (DEGs), and immune signatures were explored among different clusters. Furthermore, we developed four machine learning models based on the expression profiles of m7G-related DEGs and identified five important genes from the optimal model. We evaluated the predictive power of the 5-gene-based model using an external AD dataset (GSE44770). Results: A total of 15 genes related to m7G were found to be dysregulated in patients with AD compared to non-AD patients. This finding suggests that there are differences in immune characteristics between these two groups. Based on the differentially expressed m7G regulators, we categorized AD patients into two clusters and calculated the ESTIMATE score for each cluster. Cluster 2 exhibited a higher ImmuneScore than Cluster 1. We performed the receiver operating characteristic (ROC) analysis to compare the performance of four models, and we found that the Random Forest (RF) model had the highest AUC value of 1.000. Furthermore, we tested the predictive efficacy of a 5-gene-based RF model on an external AD dataset and obtained an AUC value of 0.968. The nomogram, calibration curve, and decision curve analysis (DCA) confirmed the accuracy of our model in predicting AD subtypes. Conclusion: The present study systematically examines the biological significance of m7G methylation modification in AD and investigates its association with immune infiltration characteristics. Furthermore, the study develops potential predictive models to assess the risk of m7G subtypes and the pathological outcomes of patients with AD, which can facilitate risk classification and clinical management of AD patients.
RESUMEN
Alzheimer's disease (AD) is a complex multifactorial disease, involving a combination of genomic, interactome, and environmental factors, with essential participation of (a) intrinsic genomic susceptibility and (b) a constant dynamic interplay between impaired pathways and central homeostatic networks of nerve cells. The proper investigation of the complexity of AD requires new holistic systems-level approaches, at both the experimental and computational level. Systems biology methods offer the potential to unveil new fundamental insights, basic mechanisms, and networks and their interplay. These may lead to the characterization of mechanism-based molecular signatures, and AD hallmarks at the earliest molecular and cellular levels (and beyond), for characterization of AD subtypes and stages, toward targeted interventions according to the evolving precision medicine paradigm. In this work, an update on advanced systems biology methods and strategies for holistic studies of multifactorial diseases-particularly AD-is presented. This includes next-generation genomics, neuroimaging and multi-omics methods, experimental and computational approaches, relevant disease models, and latest genome editing and single-cell technologies. Their progressive incorporation into basic research, cohort studies, and trials is beginning to provide novel insights into AD essential mechanisms, molecular signatures, and markers toward mechanism-based classification and staging, and tailored interventions. Selected methods which can be applied in cohort studies and trials, with the European Prevention of Alzheimer's Dementia (EPAD) project as a reference example, are presented and discussed.