PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia worldwide. In the US, it is the fifth leading cause of death in people over 65 years of age. Delineating factors that predict rate of future cognitive decline and dementia are important but are yet to be thoroughly understood. Knowledge of disease progression related biological factors will be critical in designing novel therapeutic strategies to mitigate their deleterious effects and thereby prevent the associated cognitive and behavioral decline. The research at the foundation of this R03 is a clinical translational study that uses systems biology and bioinformatics techniques to characterize the genetic and cellular context of dysregulated inflammatory pathways in the brain and periphery that impact longitudinal cognitive decline in different stage of Alzheimer's disease. Our earlier work among clinical patients at the Mild cognitive impairment stage AD suggests that a clinically meaningful degree of rapid cognitive decline was best predicted by baseline levels of an inflammatory analyte CCL2. In this work we hope to extend this initial insight by characterizing in depth the genetic drivers behind the inflammatory deregulation in clinical AD and the cellular context in which it occurs in the periphery and the central nervous system. We will confirm and validate these changes with genome wide (RNA-seq) expression changes and against data from other large national data (ADNI, Accelerating Medicines Partnership-AD) and by single cell transcriptomics of immune cells in the cerebrospinal fluid among well characterized patients. If the hypothesis and models are validated, scientific insights from this research will help identify novel therapeutic targets and individual propensities for deleterious inflammatory responses for future precision medicine interventions against neuroinflammation in AD to prevent disease progression and cognitive decline. If the hypothesis is found to be not true, the findings from this study will still represent a significant advance in our knowledge of variability in individual propensities to have a neuroinflammatory response in the face of neurodegenerative disease pathology. The results of this will be useful both clinically and in designing and interpreting future research outcomes.