ABSTRACT Alzheimer's disease (AD), the most common form of dementia, is a crippling neurodegenerative disease that is growing quickly in prevalence. Currently, there are no FDA approved medications that serve to prevent or reduce the pathology; all drugs are merely cognitive enhancers used to offset the deficits of dementia. Genome-wide association studies (GWAS) have been conducted to supplant the already acquired knowledge surrounding AD pathology and have recently identified one of several genes, Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), as a genetic node in the risk of developing AD. The main function of TREM2 significant to AD is stimulation of macrophage and neutrophil-mediated inflammatory responses, suggesting the exacerbation or alleviation of TREM2 to AD pathology is heavily based on chronic, injurious neuroinflammation as well as amyloid-β clearance. Several scientific studies published within the last five years have produced mixed results as to whether decreasing the activity of TREM2 with antibody antagonism or gene knockout mitigates or provokes the pathology of AD. Therefore, further validation of these findings is warranted, particularly pertaining to modulation of TREM2-TYROBP signaling to assess the effect of increasing phagocytosis of amyloid-β oligomers and fibrils. In order to pursue this topic, both agonistic and antagonistic small molecules were screened for and characterized for their potential to modulate TREM2-TYROBP signaling in vitro. Using an in-house developed luciferase assay validated as a robust method for assessing TREM2-TYROBP signaling in Human Embryonic Kidney cells (HEK293) transfected with a construct of both genes, we identified several hits as agonists or antagonists of TREM2-TYROBP coupling. Our next aim is to validate these hits in BV2 murine microglial cells and primary cultured murine microglia. After further characterization of these compounds in vitro, they will be tested in vivo for toxicology, bioavailability, and therapeutic efficacy in a knock-in mouse model of AD using APPNL-G-F knock-in mice. Therapeutic efficacy will be evaluated in consideration of reduced amyloid burden and reduced age-related cognitive decline as assessed with biochemistry, immunohistochemistry and behavioral examinations, respectively. Successful completion of these studies will 1) contribute to the understanding of TREM2 and its in role AD pathology and 2) present highly validated compounds as tools for further research in this area.