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, Aß42, 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.