Discovery and Validation of Key Biomarkers Based on Immune Infiltrates in Alzheimer’s Disease

Abstract

BackgroundAs the most common neurodegenerative disease, Alzheimer’s disease (AD) leads to progressive loss of cognition and memory. Presently, the underlying pathogenic genes of AD patients remain elusive, and effective disease-modifying therapy is not available. This study explored novel biomarkers that can affect diagnosis and treatment in AD based on immune infiltration.MethodsThe gene expression profiles of 139 AD cases and 134 normal controls were obtained from the NCBI GEO public database. We applied the computational method CIBERSORT to bulk gene expression profiles of AD to quantify 22 subsets of immune cells. Besides, based on the use of the Least Absolute Shrinkage Selection Operator (LASSO), this study also applied SVM-RFE analysis to screen key genes. GO-based semantic similarity and logistic regression model analyses were applied to explore hub genes further.ResultsThere was a remarkable significance in the infiltration of immune cells between the subgroups. The proportions for monocytes, M0 macrophages, and dendritic cells in the AD group were significantly higher than those in the normal group, while the proportion of some cells was lower than that of the normal group, such as NK cell resting, T-cell CD4 naive, T-cell CD4 memory activation, and eosinophils. Additionally, seven genes (ABCA2, CREBRF, CD72, CETN2, KCNG1, NDUFA2, and RPL36AL) were identified as hub genes. Then we performed the analysis of immune factor correlation, gene set enrichment analysis (GSEA), and GO based on seven hub genes. The AUC of ROC prediction model in test and validation sets were 0.845 and 0.839, respectively. Eventually, the mRNA expression analysis of ABCA2, NDUFA2, CREBRF, and CD72 revealed significant differences among the seven hub genes and then was confirmed by RT-PCR.ConclusionA model based on immune cell infiltration might be used to forecast AD patients’ diagnosis, and it provided a new perspective for AD treatment targets.

Expression of Immune Related Genes and Possible Regulatory Mechanisms in Alzheimer’s Disease

“…The cytotoxic activity of peripheral NK cells is impaired in aged individuals compared to that in young adults during aging (30). Circulating NK cell infiltration into the brain has been found in human AD and 3xTg-AD mice (6,7). NK cells exhibited enhanced pro-inflammatory profiles in the brains of 3xTg-AD mice.…”

“…Additionally, the blood-brain barrier (BBB) establishes immune privilege for the CNS immune system (4). However, infiltration of peripheral immune cells has been observed in both AD mouse models and human AD brains (5,6). Recent studies have supported the pathogenic role of circulating immune cells in AD brains.…”

Development and validation of immune-based biomarkers and deep learning models for Alzheimer’s disease

“…Then seven hub genes MRPL51, NDUFA1, NDUFS5, RPS25, SHFM1, RPA3, and MAGOH were obtained by a random forest algorithm. Among these seven hub genes, NDUFA1 and MRPL51 were considered potential biomarkers of AD in previous bioinformatics analyses (Li et al, 2018;Liu et al, 2021). NDUFA1 is an essential component of the human Frontiers in Genetics frontiersin.org respiratory chain complex I.…”

Identification of genetic molecular markers and immune infiltration characteristics of Alzheimer's disease through weighted gene co-expression network analysis

“…Alzheimer's disease is influenced by genes, environment, and aging and is clinically characterized by progressive impairment in cognitive domains, such as memory and space. Over recent years, clinical history and disease course, supplemented by histopathological and neuroimaging results, have become the new trends in diagnosing AD ( 33 , 34 ). Current research on AD has mainly focused on the gene level.…”