A Systems Approach to Targeting Innate Immunity in AD

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Summary: This proposal is for an administrative supplement to our existing grant on “A Systems Approach to Targeting Innate Immunity in AD.” We seek support for the harmonized processing and integrated analysis of genomic (GWAS/WES/WGS) and transcriptomic (bulk tissue RNAseq and sc/snRNAseq) data from multiple AMP- programs: AMP-AD, AMP-PD, AMP-RA/SLE and AMP-T2D. The overall goal is to provide novel insights into the role of the immune system in Alzheimer’s disease (AD) and to contribute to ongoing efforts aimed at identifying novel therapeutic targets. We have been members of the AMP-AD consortium since 2013 and have an in-depth knowledge of the available datasets hosted within the AD-knowledge portal. We have generated and contributed data under multiple studies, including Mayo RNAseq, MC-CAA, MCADGS, MCSA and TAUAPPms and have a thorough understanding of the data sharing process. We are/have also been leading and contributing members for multiple working groups within the AMP-AD consortium, affording us familiarity with the data hosted within the portal and the necessary experience in working with big-datasets. A major focus of our prior and ongoing work within AMP-AD is the role of the immune system in AD. In this proposal we aim to expand these efforts to investigate and identify immune signatures that are associated with AD and related disorders and comorbidities including Parkinson’s disease (PD), Type-2-diabetes (T2D), and immune disorders such as rheumatoid arthritis (RA) and lupus (SLE). To accomplish these goals we have three aims that will likewise contribute to the broader aims of the parent U01 and the consortium goal of accelerating the identification of novel therapies for AD. In Aim 1 our goal is to identify genetic variants and transcriptional networks in inflammatory pathways that are shared between as well as distinct for diseases and aging. The central hypothesis of this aim is that there are aspects of the immune system that interact with the aging process and are dysfunctional in disease, some of which will cause broader systemic disease while others may be specific to AD. Defining the aspects of immune dysfunction that contribute to AD more specifically and in the context of aging is expected to address this key knowledge gap. In Aim 2 we plan to discover inflammatory signatures that are shared between as well as tissue- specific. While AD is a neurodegenerative disease, identification of immune changes in peripheral tissues (eg. blood and kidney) that either reflect CNS changes, disease pathophysiology, or systemic immune dysfunction can have implications for furthering understanding of underlying disease etiology and have biomarker potential. In Aim 3 we will expand our analysis to determine inflammatory cell-subtype proportion and cell-specific molecular signature perturbations in disease and aging. While bulk tissue studies have provided key insights into disease such as immune activation and myelin depletion, they largely reflect gross changes within the tissue. Single cell studies are needed to evaluate molecular changes at the cellular level. We expect that comparative analysis of immune genetic and transcriptomic signatures across multiple immunity-involved diseases, tissues and cells will provide knowledge about which aspects of the immune system are benign and which may be targeted with greater effect on disease outcomes.