For simultaneously capturing the intra- and inter-regional gene-gene interactions in the LOAD or non-demented state, we constructed multi-tissue co-expression networks consisting of the top one-third (n=13,193) of the most variable gene expression traits per brain region in individuals donating tissues from all three regions (Extended Experimental Procedures). The multi-tissue co-expression network in LOAD brains indicated strong structurally segregated regions of the human brain molecular interactome (Figure 3A), generating 111 modules in the LOAD network, each containing between 30 and 1446 gene members (Figure 3A), while the network generated from non-demented samples has 89 modules ranging in size from 30 to 2278 genes. Figure 3B highlights a direct comparison of the two topological overlap matrices corresponding to the LOAD or non-demented associated network for a subset of 16 modules, demonstrating that LOAD reconfigures specific portions of the molecular interaction structure. To analytically detect and quantify this network reorganization across the demented and non-demented states, we developed a metric we refer to as modular differential connectivity (MDC) (Extended Experimental Procedures). MDC is the ratio of the average connectivity for any pair of
