Central and peripheral immune cross-talk in Alzheimer's disease and their modulation by a novel immunotherapy

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Project Summary/Abstract Alzheimer’s disease (AD) gene-risk data, epidemiological findings and animal models converge to indicate the critical role of inflammation for the onset and progression of AD. Inflammation could provide a new focus for therapeutic intervention. However, inflammation biomarkers are poorly characterized in AD. In this project, we will measure blood and cerebrospinal fluid (CSF) inflammation biomarkers and compare them to measurements of brain glial activation obtained by positron emission tomography (PET). In addition, we will determine the effect of low-dose interleukin-2 (IL-2) immunotherapy, given over 22 weeks, on these inflammation biomarkers. For this purpose, we will measure these biomarkers in AD individuals enrolled in a phase 2a safety and efficacy trial of low-dose IL-2 therapy. Regulatory T cells (Tregs) play a neuroprotective role by suppressing inflammation in the blood and the brain. We have shown that Treg immunomodulatory mechanisms are compromised in AD patients, resulting in activation of pro-inflammatory monocytes and upregulation of inflammatory mediators. In a Phase 1 clinical study, we showed that IL-2 administration induced Treg expansion and restoration; the therapy was safe, and it was associated with improved cognition. Supported by a “Part-the-Cloud” grant from the Alzheimer’s Association, we will conduct a follow up phase 2a study which includes the measurement of cognition, as well as CSF T-tau, P-tau, Aβ42, and neurofilament light chain (NFL) before and after 22 weeks of IL-2 treatment in the subjects with mild to moderate AD. Taking advantage of this novel trial, and by evaluating the 40 AD patients participating in it, the current study will investigate systemic and central nervous system (CNS) biomarkers of inflammation and their modulation by IL-2 administration. We will analyze the impact of IL-2 immunotherapy on peripheral immune biomarkers (Aim 1) as well as CNS inflammation, measured through CSF inflammation biomarkers (Aim 2) and brain inflammation positron emission tomography (Aim 3). To determine which blood biomarkers correlate best with central nervous system biomarkers (Aim 4), the associations among blood, CSF, and brain imaging measures of neuroinflammation before and after IL-2 therapy will be determined. Our novel approach will explore the potential link between systemic and CNS inflammation in AD clinical setting and advance the use of inflammatory biomarkers in AD anti- inflammatory clinical trials.