Developing a clinical and research framework for evaluating inflammation pathway dysregulation in Alzheimer's disease

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 bioinformatics and large data

analysis techniques to characterize the transcriptional and clinical context of dysregulated inflammatory pathway changes in the brain and periphery that impact longitudinal cognitive decline in different stage of AD. This information will be integrated with prior data on known biomarkers of AD to develop a clinically useful model to

focus better targeted patient care. Our earlier work among clinical AD patients at the Mild cognitive impairment stage the disease studies suggest that a clinically meaningful degree of rapid cognitive decline was best predicted by baseline levels of an inflammatory marker, 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 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 (Alzheimer's Disease Neuroimaging

Initiative, Accelerating Medicines Partnership-AD and Harvard Brain Tissue Resource Center). These results will be integrated with our knowledge of temporal changes in established AD biomarkers in different clinical stages, to develop a clinically useful framework. The scientific insights and clinical models from this research will help

target novel inflammation based therapeutic targets in the most effective stage of AD among clinical patients after taking into account individual variability for deleterious inflammatory responses. This is a much needed step for future precision medicine interventions against neuroinflammation in AD to prevent disease progression.