Introduction: Cerebral cortex is the largest region of  brain playing key roles in several functions involved in cognition and neuroplasticity. In brain of Down syndrome reduction of size and diminishing of number of neuron density and synaptic connections was associated with impairment of cognition and reducing of neuroplasticity. Objective: To analyze the differential expression of 72 genes associated with neuroplasticity in several structures of cerebral cortex of Down syndrome. Methodology: From a DNA microarray platform GSE59630 deposited in GEO database, Z-scores for 72 neuroplasticity associated genes were compared between 58 DS and 58 control samples in eleven structures of brain cortex. Results: The median of Z-score values of genes associated to neuroplasticity expressed in several structures of brain cortex showed differential expression by gene and by cortex structure. In hippocampus, differential expression was recorded for EGR1, SMYD4, PCDH20, and VEGFA. Expression in somatosensory cortex showed significant lowest Z-score values for SERPIB8, SHMT1 and THBSH3 genes. In superior temporal cortex, the most under expressed genes in Down syndrome were, BDNF, RGS8 and SERINC2. Finally, in visual cortex, ADIPOQ, and TSPAN5 were the most under-expressed genes in DS patients. Discussion: Under-expression in hippocampus of genes which are associated with cognition and neuroplasticity showed a regionally differential regulation that correlates with a functional systemic imbalance of Down syndrome brain cortex neuroplasticity proteostasis network. Moreover, our results open the possibility to develops potential novel therapeutic strategies to management the hippocampal plasticity