Investigating whole-body innate immune activation in Alzheimer's disease using PET imaging and immune profiling

Project Summary/Abstract The emerging role of inflammation in the pathogenesis of Alzheimer’s disease (AD) is shifting how the field is approaching its treatment, with growing interest in the development of immunomodulatory therapeutics. The appropriate therapeutic window and patient population for such treatment strategies remains to be determined. Importantly, current understanding of inflammation in AD has largely arose from brain tissues studied in isolation. However, it has become clear that peripheral inflammatory responses may influence both AD risk and disease progression. Here, I propose to use whole-body positron emission tomography (PET) of the translocator protein 18kDa (TSPO) and triggering receptor on myeloid cells 1 (TREM1) and complementary immune profiling techniques to non-invasively assess peripheral and central inflammation in Alzheimer’s disease. This project aims to use parallel preclinical (Aim 1) and clinical approaches (Aims 2 & 3) to increase the fundamental understanding of inflammation in disease while actively improving clinical assessment. Our specific aims are (1) to characterize distinct peripheral and central myeloid cell responses and investigate the effects of systemic inflammation on neuroinflammation in the 5XFAD mouse model of AD; (2) to develop a clinically feasible approach to quantify whole-body TSPO-PET uptake in AD patients; and (3) to study whole-body immune signatures associated with disease severity in AD and mild cognitive impairment patients using whole-body TSPO-PET and blood-based immune profiling. The innovation of this work lies in the whole-body approach for the investigation of inflammation in AD, which has yet to be investigated. TREM1-PET is the first tool to specifically image proinflammatory peripheral myeloid cells in vivo. Preclinical investigation using TREM1-PET and clinical application of whole-body TSPO-PET imaging in patients will provide novel insights into the complex neuroimmune interactions involved in AD pathogenesis. The significance of this work is that enhanced understanding of whole-body innate immune responses in AD has the potential to not only improve diagnosis and disease monitoring, but also to develop and screen for effective disease modifying therapeutics. Additionally, these methods can be applied to impact our understanding of inflammation across a broad range of inflammatory and neurological disorders.