Immune activation in LOAD may have multi-faceted activity: long-term use of non-steroid anti-inflammatory drugs (NSAIDs) before onset of the disease decreases risk (Etminan et al., 2003), and microglia effector function via interfering with reactive oxygen production, cytokines and complement cascade members have been postulated to damage healthy neurons and synapses (Cameron and Landreth, 2010). Close association and positive feedback between amyloid-β and microglia (Meyer-Luehmann et al., 2008) further clouds the cause and effect relationships of inflammation to disease progression. Without a causal framework for these observations, it is difficult to find optimal molecular targets that direct LOAD inflammation. Therefore, we integrated clinical factors with whole-genome genotype and molecular trait data to identify a network module containing several microglia signaling cascades functionally related to the reactive oxygen burst during pathogen phagocytosis. We highlight the causal regulator TYROBP that exerts control over multiple genes within this module and pathways involved in LOAD, thus validating our network structure and its relevance to LOAD pathology. This approach appears to offer novel insights for drug discovery programs that can affect neurodegenerative diseases, such as LOAD.
