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.

Project Narrative (Relevance) This research is relevant to public health because Alzheimer’s disease (AD)/dementia is the 6th leading cause of death and affects more than 5 million people in the USA, yet no disease-modifying drugs are available. A growing number of studies reveal a link between diabetes and AD, which has been a hot topic to focus on insulin resistance and glucose metabolism perturbation with AD disease pathology. The proposed project will identify potential causal genes in glucose transporters, co-transporters, and insulin signaling pathway genes in the brain and potential other glucose metabolism genes across all tissues using transcriptome-wide association study (TWAS). Additionally, we will construct a co-expression network biological pathway associated with glucose metabolism in AD/dementia utilizing proteomics associated with glucose metabolism. All the analyses will be performed using well-established large UK Biobank data.