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Background  Cerebral amyloidosis, neuroinflammation, and tauopathy are key features of Alzheimer’s disease (AD), but interactions among these features remain poorly understood. Our previous multiscale molecular network models of AD revealed  TYROBP  as a key driver of an immune- and microglia-specific network that was robustly associated with AD pathophysiology. Recent genetic studies of AD further identified pathogenic mutations in both  TREM2  and  TYROBP .    Methods  In this study, we systematically examined molecular and pathological interactions among Aβ, tau, TREM2, and TYROBP by integrating signatures from transgenic  Drosophila  models of AD and transcriptome-wide gene co-expression networks from two human AD cohorts.    Results  Glial expression of TREM2/TYROBP exacerbated tau-mediated neurodegeneration and synergistically affected pathways underlying late-onset AD pathology, while neuronal Aβ42 and glial TREM2/TYROBP synergistically altered expression of the genes in synaptic function and immune modules in AD.    Conclusions  The comprehensive pathological and molecular data generated through this study strongly validate the causal role of  TREM2/TYROBP  in driving molecular networks in AD and AD-related phenotypes in flies.    Electronic supplementary material  The online version of this article (10.1186/s13073-018-0530-9) contains supplementary material, which is available to authorized users.

Integrated biology approach reveals molecular and pathological interactions among Alzheimer’s Aβ42, Tau, TREM2, and TYROBP in Drosophila models