PROJECT SUMMARY Dysregulation of innate immunity is thought to be a significant contributor to Alzheimer’s disease (AD) pathogenesis. We have focused on harnessing innate immunity via Toll-like receptor 9 (TLR9) to modulate age- related defects in immune cells to counteract AD pathology. Our findings from multiple AD pathology transgenic mouse models provide the first in vivo evidence that stimulation of innate immunity with TLR9 agonist CpG ODN can reduce behavioral deficits and ameliorate all pathological hallmarks of AD. Most current immunotherapeutic trials for AD have been associated with a major complication referred to as amyloid-related imaging abnormalities (ARIA), which is linked to the presence and extent of cerebral amyloid angiopathy (CAA). CAA is present in a majority of individuals with AD, and its severity is an independent risk factor for cognitive decline. Hence, it is critical to develop a therapy effective against CAA without inducing ARIA complications. Additionally, the premature translation of promising transgenic mice data directly to patients has been associated with a very high clinical trial failure rate. Our recent study established that squirrel monkeys (SQMs), an NHP model that develops extensive age-dependent CAA unlike other primates, represent an opportune environment for demonstrating the therapeutic benefits of our immunomodulation using CpG ODN 2006. Here we propose the use of class B CpG 1018, which is currently being tested in clinical trials for a variety of indications. The collective studies are designed to provide a comprehensive portrayal of CpG 1018 efficacy and long-term safety by integrating biofluid biomarker signatures with imaging markers, cognitive measures, in addition to neuropathology correlates. Disease progression and safety will also be monitored by a combination of MRI techniques, which will enable morphometric characterization and screening for ARIA. The utility of a multi-shell diffusion MRI model to follow CpG 1018’s treatment effects in vivo on brain microstructural integrity, especially WM integrity changes, will be validated for the first time. An additional strength of this proposal is the use of our powerful proteomic strategy to unveil the first comprehensive characterization of the CAA and choroid plexus (CP) proteomes in association with disease progression and CpG 1018 intervention. This localized proteomic approach is a preferred method as it combines unbiased mass spectrometry examination with laser capture microdissection to precisely excise defined neuropathological lesions. A further aim of this study is to map involvement of the CP-CSF system in immune cell trafficking in response to CpG 1018. Delineating the CAA and CP protein signatures will advance understanding of CpG 1018’s favorable immunomodulatory capabilities, as well as provide insights into CAA pathogenesis to improve diagnostic capability. Overall, the interventions described here will provide essential preclin...