Machine learning identification and immune infiltration of disulfidptosis‐related Alzheimer's disease molecular subtypes

Abstract

BackgroundAlzheimer's disease (AD) is a common neurodegenerative disorder. Disulfidptosis is a newly discovered form of programmed cell death that holds promise as a therapeutic strategy for various disorders. However, the functional roles of disulfidptosis‐related genes (DRGs) in AD remain unknown.MethodsMicroarray data and clinical information from patients with AD and healthy controls were downloaded from the Gene Expression Omnibus database. A thorough examination of DRG expression and immune characteristics in both groups was performed. Based on the identified DRGs, we performed an unsupervised clustering analysis to categorize the AD samples into various disulfidptosis‐related molecular clusters. Weighted gene co‐expression network analysis was performed to select hub genes specific to disulfidptosis‐related AD clusters. The performances of various machine learning models were compared to determine the optimal predictive model. The predictive ability of the optimal model was assessed using nomogram analysis and five external datasets.ResultsEight DRGs showed differential expression between the AD and control samples. Two different molecular clusters were identified. The immune cell infiltration analysis revealed distinct differences in the immune microenvironment of the two clusters. The support vector machine model showed the highest performance, and a panel of five signature genes was identified, which showed excellent performance on the external validation datasets. The nomogram analysis also showed high accuracy in predicting AD.ConclusionWe identified disulfidptosis‐related molecular clusters in AD and established a novel risk model to assess the likelihood of developing AD. These findings revealed a complex association between disulfidptosis and AD, which may aid in identifying potential therapeutic targets for this debilitating disorder.

Disulfidptosis: A new type of cell death

“…Following the discovery of disulfidptosis, extensive research has been conducted to determine its role in a range of physiological and pathological conditions. Preliminary studies suggest that disulfidptosis plays a role in the pathogenesis of diseases including cancer [2,5,6,[114][115][116], neurodegenerative diseases [7,8], cardiovascular diseases [9], and liver diseases [10][11][12]. For instance, in cancer cells, altered metabolism often leads to glucose Fig.…”

“…Abbreviations: FASL, factor-related apoptosis ligand; TRAIL, TNFrelated apoptosis-inducing ligand; TNF, tumor necrosis factor; IFN-1, interferon-1; MLKL, mixed lineage kinase domain-like protein; RIPK1, receptor-interacting protein kinase 1; RIPK3, receptor-interacting protein kinase 3; PGAM5, phosphoglycerate mutase family 5; KEAP1, Kelch-like ECH-associated protein 1; NRF2, nuclear factor erythroid 2 related factor 2; PARP-Q, poly-ADP-ribose polymerase; NAD + , nicotinamide adenine dinucleotide insufficiency, which can trigger disulfidptosis in cells with high SLC7A11 expression [2,5,6,[114][115][116]. Similarly, pathological changes related to disulfidptosis have been observed in neurodegenerative diseases such as Alzheimer's disease [7,8].…”

“…Modulating immune system functions can prevent autoimmune diseases [13][14][15]. Moreover, targeting disulfidptosis pathways may lead to treatment strategies for other diseases caused by oxidative stress imbalances, such as neurodegenerative [7,8] and inflammatory diseases [9].…”

“…Recent studies indicate that disulfidptosis is also related to neurodegenerative diseases [7,8]. In certain neurodegenerative diseases, the expression level of SLC7A11 is markedly higher than that in normal cells [118].…”

“…Recent studies have suggested that disulfidptosis plays a significant role in the onset and progression of various diseases. Associations have been observed with cancer [2,5,6], neurodegenerative diseases [7,8], cardiovascular diseases [9], and liver diseases [10][11][12], and other conditions are closely related to disulfidptosis [13][14][15].…”