Functional neurogenomics is the interface between neurosciences knowledge and Omics sciences data. It characterizes, identifies, and analyzes expression of genes involved in the function of several structures of brain and cognition. Its major goal is to understand the main pathways of brain function, plasticity, and the etiopathogenesis of brain diseases. We have done an integrate analysis of global brain gene expression linked to cognitive disability in Down syndrome. It is a new approach to better understand the control of complex brain networks of gene expression involved in this syndrome. The objective of the chapter is to present computationally simulate data of global expression of 108 genes associated with cognitive disability and neuroplasticity from DNA microarray experiments of postmortem brain from normal controls and patients with Down syndrome. Some genes that were studied are involved in metabolic process and also promote hippocampal plasticity; interventions reawaken the neural plasticity may permit improved cognition. One of the striking findings was that some of the causes of dysregulation appear to result in the brain being trapped in an immature state of synaptic development. Understanding the functional neurogenomics of Down syndrome brain, emerge a new scenario to partially overcome cognitive disability through new prospective genomic therapies.