The fusiform gyrus exhibits differential gene-gene co-expression in Alzheimer's disease

Abstract

Alzheimer's Disease (AD) is an irreversible neurodegenerative disease clinically characterized by the presence of β-amyloid plaques and tau deposits in various regions of the brain. However, the underlying factors that contribute to the development of AD remain unclear. Recently, the fusiform gyrus has been identified as a critical brain region associated with mild cognitive impairment, which may increase the risk of AD development. In our study, we performed gene co-expression and differential co-expression network analyses, as well as gene-expression-based prediction, using RNA-seq transcriptome data from post-mortem fusiform gyrus tissue samples collected from both cognitively healthy individuals and those with AD. We accessed differential co-expression networks in large cohorts such as ROSMAP, MSBB, and Mayo, and conducted over-representation analyses of gene pathways and gene ontology. Our results comprise four exclusive gene hubs in co-expression modules of Alzheimer's Disease, including FNDC3A, MED23, NRIP1, and PKN2. Further, we identified three genes with differential co-expressed links, namely FAM153B, CYP2C8, and CKMT1B. The differential co-expressed network showed moderate predictive performance for AD, with an area under the curve ranging from 0.71 to 0.76 (+/- 0.07). The over-representation analysis identified enrichment for Toll-Like Receptors Cascades and signaling pathways, such as G protein events, PIP2 hydrolysis and EPH-Epherin mechanism, in the fusiform gyrus. In conclusion, our findings shed new light on the molecular pathophysiology of AD by identifying new genes and biological pathways involved, emphasizing the crucial role of gene regulatory networks in the fusiform gyrus.

Keywords: Alzheimer's disease; brain tissue; co-expression networks; differential co-expression networks; fusiform gyrus; hub genes; regulatory networks.

Figure 1

General distribution of genes from both co-expression and differential co-expression analysis. (A) Simplified representation of co-expressed gene hubs and their respective gene modules identified by CEMiTool in the fusiform gyrus of Alzheimer's disease. (B) Distribution of co-expressed genes across each condition. (C) Distribution of co-expressed gene hubs across each condition. (D) The overall intersection of co-expressed gene hubs in AD, differential co-expressed genes (DCG), and genes with differential co-expressed links (DCL) in AD.

Figure 2

Distribution of over-represented pathways across each condition. (A) Overall functional enrichment analysis highlights 11 pathways with statistical significance (FDR <= 0.05) in Alzheimer's Disease. (B) Table with significant pathways for Alzheimer's Disease group and its respective modules.

Figure 3

Differential co-expression Network. (A) Differential co-expressed sub-network identified by diffcoexp with 65 genes and 47 differential expressed links. The three highly connected DCGs are highlighted as orange nodes. (B) STRING database highlights a multi-edge protein-protein interaction sub-network for differentially expressed genes. Different colors in edges represent evidence of interaction based on co-expression. Most importantly, these interactions are evidenced by curated databases (pink edges) and experimentally determined (black edges). (C) Stability (accuracy) of DCGs after the 100-fold sample bootstrap tests. (D) Baseline expression level of the three identified DCGs on 13 tissues of normal brains cataloged in GTEx. (E) Test AUC mean and Test error mean of 5-fold cross-validation of XGboost regarding sets of genes. (F) Pairwise Adjusted Mutual Information for differential gene co-expression networks.