Computational analysis of gene expression profiles of moderate to severely affected Alzheimer’s disease (AD) patients (Zhang et al., Cell, 2013) indicates that DAP12/TYROBP is an important “hub” or “driver” for the pathogenesis of typical, late-onset, sporadic AD. This is the first genetic risk factor for this common form of the illness to be predicted by this new “big data” approach. Conveniently, this prediction dovetails well with a potent risk factor, TREM2, recently identified to be mutated in some patients with late-onset AD. In those patients, some TREM2 mutations appear to be equipotent with APOE4 in risk causation (i.e., RR=3). This is notable because some have predicted that APOE4 is the most potent risk factor that will ever be identified in AD. The computations network approach forms the core of the recently created multi-institutional National Institute on Aging Accelerating Medicines Partnership (NIA AMP-AD) program. Herein, we propose comprehensive studies of genetically manipulated mouse brain neurons and microglia in order to advance our understanding of how the DAP12/TYROBP/TREM2 system exerts effects on AD risk. The specific aim of this proposal is to characterize brain and microglial gene expression in mice that express a severe amyloid-forming phenotype and also are deficient in either DAP12 or TREM2. These mice were chosen because their pathological phenotype would be predicted to be the most similar to the pathology of the brains studied in the Zhang et al. Cell 2013 paper.