As observed in previous network-based studies (Chen et al., 2008; Emilsson et al., 2008; Zhang and Horvath, 2005), we find that the brain gene expression is organized into modules of distinct functional categories (Figure 3C). Over-representation of canonical pathways and biological processes in modules was measured through Fisher’s exact test (FET), corrected for number of modules and functional categories tested. Figure 3C highlights significant over-representation of functional categories in modules showing GOC, LOC or conserved connectivity and containing at least 50 genes. The multi-factorial basis of LOAD neuropathology involves biological processes active in both the CNS and the metabolic and vascular peripheral system that have often progressed silently for many years (Huang and Mucke, 2012; Murray et al., 2011). In fact, we find that multiple functional categories are highly enriched in the LOAD-associated modules, including the immune response, unfolded protein, vascular system, extracellular matrix, neurogenesis (brain development), glucose homeostasis, synaptic transmission and olfactory sensory perception categories in the GOC modules (Figure 3C), while the LOC modules are enriched for genes involved in nerve myelination, cell-cycle, γ-aminobutyricacid (GABA) metabolism, and neurotrophin
