Abstract
Background: Recent research indicates that lipid metabolism and autophagy play crucial roles in the development of Alzheimer's disease (AD). Investigating the relationship between AD diagnosis and gene expression related to lipid metabolism, autophagy, and lipophagy may improve early diagnosis and the identification of therapeutic targets. Methods: Transcription datasets from AD patients were obtained from the Gene Expression Omnibus (GEO). Genes associated with lipid metabolism, autophagy, and lipophagy were sourced from the Gene Set Enrichment Analysis (GSEA) database and the Human Autophagy Database (HADb). Lipophagy-related hub genes were identified using a combination of Limma analysis, weighted gene co-expression network analysis (WGCNA), and machine learning techniques. Based on these hub genes, we developed an AD risk prediction nomogram and validated its diagnostic accuracy using three external validation datasets. Additionally, the expression levels of the hub genes were assessed through quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: Our analysis identified three hub genes-ACBD5, GABARAPL1, and HSPA8-as being associated with AD progression. The nomogram constructed from these hub genes achieved an area under the curve (AUC) value of 0.894 for AD risk prediction, with all validation sets yielding AUC values greater than 0.8, indicating excellent diagnostic efficacy. qRT-PCR results further corroborated the associations between these hub genes and AD development. Conclusions: This study identified and validated three lipophagy-related hub genes and developed a reliable diagnostic model, offering insights into the pathology of AD and facilitating the diagnosis of AD patients.