Gene Set Index Based on Different Modules May Help Differentiate the Mechanisms of Alzheimer's Disease and Vascular Dementia

Abstract

Purpose: Alzheimer's disease (AD) and vascular dementia shared similar symptoms, the aim of the present study was to identify potential differences in the mechanisms underlying the two diseases.

Materials and methods: The data set including AD, vascular dementia, and control samples was carried out gene differential expression analysis, weighted gene co-expression network analysis, functional enrichment, protein-protein interaction network construction, and least absolute shrinkage and selection operator analysis to reveal the differences in the mechanisms underlying the two diseases and potential diagnostic gene signature.

Results: We identified the gene modules related to AD or vascular dementia. Enrichment analysis of module genes and construction of a protein-protein interaction network suggested that the "brown" module may be involved in a chemokine pathway, the "blue" module may be involved in cortisol synthesis and secretion, and the "turquoise" module may be involved in cholinergic synapse transmission. The hub gene-based signature index may be a biomarker of AD and vascular dementia and may even differentiate the two diseases from each other with high area under curve.

Conclusion: Our results identified not only core pathways involved in both AD and vascular disease, but also their potentially specific pathways. We proposed the hub gene-based signature index may be useful for diagnosing AD and vascular dementia.

Keywords: Alzheimer’s disease; LASSO; WGCNA; vascular dementia; weighted gene co-expression network analysis.

Figure 1

Flow chart of study design. AD, Alzheimer’s disease; LASSO, least absolute shrinkage and selection operator; ROC, receiver operating characteristic curve; TF, transcription factor.

Figure 2

Differentially expressed gene (DEG) analysis and Weighted Gene Co-Expression Network Analysis. (A) Manhattan map of differential gene expression. (B) Definition of power related to modules. (C) Recognition module. (D) The brown module positively correlated with both AD and vascular dementia, the blue module negatively correlated with vascular dementia, and the turquoise module negatively correlated with AD. The grey module did not correlate with either type of dementia. (E) Module membership and gene significance strongly correlated with each other within each module.

Figure 3

Results of functional enrichment. (A) Biological processes involving genes of the blue module. (B) KEGG pathways involving genes of the blue module. (C) Biological processes involving genes of the brown module. (D) KEGG pathways involving genes of the brown module. (E) Biological processes involving genes of the turquoise module. (F) KEGG pathways involving genes of the turquoise module.

Figure 4

Enrichment analysis using ClueGo. Biological processes significantly enriched in the (A) blue, (B) brown or (C) turquoise modules.

Figure 5

Result of gene set enrichment analysis. (A) Biological processes enriched in AD. (B) Biological processes enriched in vascular dementia. (C) KEGG pathways enriched in AD. (D) KEGG pathways enriched in vascular dementia.

Figure 6

Integrated regulation of AD or vascular dementia by maladjustment of hub gene expression of modules. (A) Integrated regulatory network of gene pathways. (B–D) Maps of gene-pathway correlations in the (B) blue, (C) brown, or (D) turquoise module.

Figure 7

Potential transcription factor-target gene interactions in AD and vascular dementia. (A) Docking of ITGB2 and the transcription factor SPI1. (B) Docking of EGFR and the transcription factor YBX1. (C) Docking of INS and the transcription factor PAX4. (D–F) Potential regulation of genes in the (D) brown, (E) blue or (F) turquoise modules. Up-regulated genes are red; down-regulated genes, blue.

Figure 8

Assessment of models for identifying AD and vascular dementia. (A–C) LASSO model. (D–F) Receiver operating characteristic curves for differentiating (D) AD patients and non-demented controls, (E) vascular dementia patients and non-demented controls, or (F) patients with AD or vascular dementia. AUC, area under the curve.