System biology approach to decode molecular mechanism of glucose metabolism in AD and dementia

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Project Summary/Abstract Alzheimer’s disease (AD) and dementia affect 50 million worldwide and numbers expected to triple by 2050. AD is the 6th leading cause of death and affects more than 5 million in the USA alone. Despite substantial efforts, the biochemical and cellular changes in the brain of AD remain incompletely understood and no disease- modifying drugs are available yet. However, a growing number of studies reveal a link between disrupted glucose metabolism and neuronal cell death in AD/dementia. High glucose levels increased brain cell damage and promoted the formation of amyloid plaques and tau tangles, and a reduction in glycolysis lead to severe form of dementia. The alteration of GLUT (Glucose transporter), SGLT (sodium-dependent co-transporters), and insulin signaling pathway were reported in the brain of AD/dementia. However, the consequences of these alterations in the brain and the association with peripheral glucose metabolism and AD/dementia remain controversial. Given the high prevalence of type 2 diabetes in the older adults (28% in the USA), this topic is timely and significant for further in-depth knowledge. Thus, we propose to interrogate the systemic molecular mechanism of glucose metabolism in AD/dementia using a well-established large cohort, UK biobank (n=500,000) via Transcriptome-Wide Association Study (TWAS) and co-expression network biological pathway analysis with proteomics. TWAS integrates GWAS and expression quantitative trait loci (eQTL) increasing the power to predict gene expression levels and to enable solid interpretations of gene-trait associations. We have two specific aims; 1) Estimate predicted glucose metabolism gene expressions associated with AD/dementia. We will use a TWAS approach via GLUT, SGLT, and insulin signaling pathways in the brain and whole genome-wide analysis across all tissues using PrediXcan algorithm which uses GTEx RNA-seg and eQTL data for its model development. 2) Determine glucose metabolism molecular pathways and targets associated with AD/dementia. We will construct co-expression networks of proteomics that are associated with glucose metabolism genes via Weighted Gene Co-expression Network Analysis (WGCNA) and present highly significant hub module and driver proteins to elucidate multi-layered biological and molecular therapeutic targets for AD/dementia. Our proposal can provide fundamental knowledge in enhancing the understanding of early disease initiation and progression of AD/dementia and to enlist reliable molecular targets for the acceleration of drug discovery or repurposing.