PICALM and Alzheimer disease: Based on the assumption that functional interactive co-evolution could be maintained through complementary mutations over evolutionary history [27, 30], findings from a protein-protein network that used polygenetic distance metrics of a large-scale high-throughput protein-protein interaction dataset have suggested that Alzheimer’s disease (AD) associated genes, PICALM, BIN1, CD2AP, and EPHA1 demonstrate evidence of a pattern of co-evolution [29].