Identification of Autophagy-Related Candidate Genes in the Early Diagnosis of Alzheimer's Disease and Exploration of Potential Molecular Mechanisms.

Abstract

This study aimed to identify autophagy-related candidate genes for the early diagnosis of Alzheimer's disease (AD) and elucidate their potential molecular mechanisms. Differentially expressed genes (DEGs) and phenotype-associated significant module genes were obtained using the "limma" package and weighted gene co-expression network analysis (WGCNA) based on hippocampal tissue datasets from AD patients and control samples. The intersection between the list of autophagy-related genes (ATGs), DEGs, and module genes was further investigated to obtain AD-autophagy-related differential expression genes (ATDEGs). Subsequently, the least absolute shrinkage and selection operator (LASSO) algorithm was utilized to identify hub genes, and a second intersection was performed with important module genes from the protein-protein interaction (PPI) network to obtain co-hub genes. Finally, a diagnostic model was constructed by receiver operating characteristic (ROC) analysis to determine the candidate genes with high diagnostic efficacy in the external validation set. Moreover, immune infiltration analysis was performed on AD patient brain tissues and explore the correlation between candidate genes and immune cells. We further analyzed the expression level of candidate genes in the SH-SY5Y cells with Aβ25-35 (25µM). Among the 17 identified AD-ATDEGs, ATP6V1E1 stood out with area under the curve (AUC) values of 0.869, 0.817, and 0.714 in the external validation set, underscoring its high diagnostic efficacy in both hippocampal and peripheral blood contexts for AD patients. Meanwhile, ATP6V1E1 expression was positively correlated with effector memory CD4 + T cells, while negatively correlated with natural killer T cells and activated CD4 + T cells. Results from quantitative PCR (qPCR) and immunofluorescence assays indicated a reduction in ATP6V1E1 expression, aligning with our database analysis findings. In summary, ATP6V1E1 as a candidate gene provides a new perspective for the early identification and pathogenesis of AD.