ABSTRACT Human genome-wide association studies and work in Alzheimer’s disease animal models have begun to uncover pivotal roles for TREM2, CD33, and CD22 in Alzheimer’s disease and other forms of age-related dementia. While increasing evidence indicates that these innate immune receptors are critically involved in Alzheimer’s disease progression, we still lack in-depth understanding of the intracellular signaling molecules employed by these immune receptors to influence neurodegenerative disease. Identification of the signaling pathways involved in the immune response to Alzheimer’s disease will help to reveal novel therapeutic targets and also provide new insights into neurodegenerative disease pathoetiology. The SYK-CARD9 signaling axis has been shown to control immune responses downstream of TREM2, CD33, and CD22 in other models of disease, although its role in Alzheimer’s disease and most other neurodegenerative disorders still remains to be determined. In our preliminary studies, we have found that genetic ablation of CARD9 in an amyloid beta (Ab)-mediated mouse model of Alzheimer’s disease results in exacerbated cognitive decline, increased Ab deposition, and impaired activation of microglia. We also show that disruption of either CARD9 or SYK leads to impaired phagocytosis of Ab and other forms of neurotoxic debris associated with neurodegeneration. In further support of a role for SYK in Alzheimer’s disease, recent in vitro studies have shown that Ab stimulation of macrophages promotes potent activation of SYK signaling. Given these preliminary findings and others showing that SYK and CARD9 are almost exclusively expressed by microglia in the brain, we hypothesize that the SYK-CARD9 signaling axis helps to limit Ab-mediated neurological disease by promoting neuroprotective functions in brain-resident macrophages. Leveraging a combination of unique transgenic mouse strains and human-induced pluripotent stem cells derived from patients harboring loss-of-function CARD9 mutations, we will uncover how the SYK-CARD9 signaling axis influences neurological disease in AD mouse models. Moreover, we will test whether therapeutic treatment with known activators of the SYK-CARD9 signaling pathway is effective in limiting Ab-mediated disease progression. Completion of the studies proposed in this application will break new ground in our understanding of the molecular signaling pathways used by the innate immune system in Ab-mediated neurological disease and will help to establish new molecular players that can be targeted in Alzheimer’s disease.