Identification of Blood-Based Glycolysis Gene Associated with Alzheimer’s Disease by Integrated Bioinformatics Analysis

Article type: Research Article

Authors: Wang, Fang^{a; b} | Xu, Chun-Shuang^a | Chen, Wei-Hua^a | Duan, Shi-Wei^a | Xu, Shu-Jun^a | Dai, Jun-Jie^c | Wang, Qin-Wen^{a; *}

Affiliations: [a] Zhejiang Provincial Key Laboratory of Pathophysiology, School of Medicine, Ningbo University, Ningbo, China | [b] Zhejiang Pharmaceutical College, Ningbo, China | [c] Affiliated Lihuili Hospital of Ningbo University, Ningbo, China

Correspondence: [*] Correspondence to: Qin-wen Wang, 818 Fenghua Road, Jiangbei District, Ningbo, Zhejiang, China. Tel.: +86 13486485004; E-mail: [email protected].

Abstract: Background:Alzheimer’s disease (AD) is one of many common neurodegenerative diseases without ideal treatment, but early detection and intervention can prevent the disease progression. Objective:This study aimed to identify AD-related glycolysis gene for AD diagnosis and further investigation by integrated bioinformatics analysis. Methods:122 subjects were recruited from the affiliated hospitals of Ningbo University between 1 October 2015 and 31 December 2016. Their clinical information and methylation levels of 8 glycolysis genes were assessed. Machine learning algorithms were used to establish an AD prediction model. Receiver operating characteristic curve (AUC) and decision curve analysis (DCA) were used to assess the model. An AD risk factor model was developed by SHapley Additive exPlanations (SHAP) to extract features that had important impacts on AD. Finally, gene expression of AD-related glycolysis genes were validated by AlzData. Results:An AD prediction model was developed using random forest algorithm with the best average ROC_AUC (0.969544). The threshold probability of the model was positive in the range of 0∼0.9875 by DCA. Eight glycolysis genes (GAPDHS, PKLR, PFKFB3, LDHC, DLD, ALDOC, LDHB, HK3) were identified by SHAP. Five of these genes (PFKFB3, DLD, ALDOC, LDHB, LDHC) have significant differences in gene expression between AD and control groups by Alzdata, while three of the genes (HK3, ALDOC, PKLR) are related to the pathogenesis of AD. GAPDHS is involved in the regulatory network of AD risk genes. Conclusion:We identified 8 AD-related glycolysis genes (GAPDHS, PFKFB3, LDHC, HK3, ALDOC, LDHB, PKLR, DLD) as promising candidate biomarkers for early diagnosis of AD by integrated bioinformatics analysis. Machine learning has the advantage in identifying genes.

Keywords: Alzheimer’s disease, DNA methylation, glycolysis gene, machine learning

DOI: 10.3233/JAD-210540

Journal: Journal of Alzheimer's Disease, vol. 83, no. 1, pp. 163-178, 2021