ABSTRACT The identification of novel therapeutic targets for Alzheimer's disease is necessary to reach the goal of the National Alzheimer's Project Act (NAPA) of having an effective treatment in place by 2025. Despite numerous promising therapeutic approaches identified pre-clinically to treat Alzheimer's disease, the translation of these therapies to the clinic have been incredibly disappointing. The vast number of population genetic studies that have been performed for AD present an opportunity to identify disease pathways what could be targeted therapeutically. One gene that has a strong effect on AD risk is the triggering receptor expressed on myeloid cells-2 (TREM2). As the name implies, TREM2, is an innate immune receptor expressed on microglia, known to signal through DAP12 to trigger phagocytosis. TREM2 SNPs have been identified as significantly increasing risk of AD in GWAS studies. The hypothesis for this increased risk is that there is a loss of function, impairing the innate immune system to clear amyloid deposition efficiently. We hypothesize that targeting TREM2 to activate the receptor will modulate the neuroinflammatory response and stimulate microglia to phagocytose and clear the amyloid deposits. Furthermore, we hypothesize that activating the TREM2 receptor to modulate the neuroinflammatory response will ameliorate tau pathology, provide neuroprotection, and avoid cerebrovascular adverse events associated with Aβ targeted therapies. To activate the TREM2 receptor, we are using an antibody developed by Alector, LLC, Alector-002a, that recognizes TREM2 and activates the receptor. We have found that the antibody show immune modulation, clearance of amyloid deposits, and cognitive improvement in amyloid depositing mice. We propose three specific aims to test our hypothesis: Specific Aim 1: Determine the neuroinflammatory, amyloid lowering and cognitive effects of A-002a. Specific Aim 2: Determine the tau modifying, neuroprotective and cognitive effects of A-002a. Specific Aim 3: Determine the potential for cerebrovascular adverse events of A-002a.

PROJECT NARRATIVE Alzheimer's disease remains an incurable condition in desperate need of novel, disease-modifying. Genetic studies have identified the TREM2 gene as a risk gene for Alzheimer's and we propose to test a therapeutic targeting TREM2. We have found that our approach lowers amyloid deposits, and improves cognition in a mouse model of amyloid pathology and we will test the effects of this approach on other aspects of Alzheimer's pathologies.