gene membership for the different regional specific immune modules ranges from 386 in CB to 1108 in the PFC, with 247 of the genes in the CB detected in all regions (P=1e-19). The identity of the key causal regulators is somewhat variable across each brain regional version of the microglia module of which CTSC, HCK, TYROBP, SERPINA1, S100A11, LY86, DOCK2 and FCER1G were common to all immune modules, regardless of brain region. Through the combined ranking score based on regulatory strength and differential expression in PFC of LOAD brains, TYROBP scored the highest (Figure S4A). Table 1 lists the 20 top ranking PFC modules and their respective key causal regulators. Expression of TYROBP is restricted to cells involved in the innate immunity including the microglial cells in the brain (Schleinitz et al., 2009). Here, TYROBP was significantly up-regulated in LOAD brains in the HBTRC sample (1.18 fold, P = 0.028) and the direction of this effect was replicated (1.17 fold, P = 5.1e-05) in an independent multi-center cohorts study (see Extended Experimental Procedures and Figure S4B). Additionally, we observed a progression of TYROBP expression changes across mild cognitive impairment (MCI) in the replication study (Figure S4B). Estimating what constitutes a
