Understanding the molecular and cellular processes that cause dementia is one of the most important challenges in neuroscience. SUMOylation is a post-translational protein modification that has been strongly implicated in neurodegenerative diseases. To investigate SUMOylation in dementia we profiled the expression of key SUMOylation pathway proteins in post mortem brain tissue from Alzheimer’s Disease (AD) and Down’s Syndrome (DS) patients. As expected, both AD and DS tissue displayed massively increased levels of phosphorylated tau compared to age- and sex-matched controls. Surprisingly, there were no changes in the levels of the E1 and E2 enzymes required for protein SUMOylation, or in levels of the deSUMOylating enzyme SENP1. There was, however, a marked decrease in the SUMO-2/3-specific deSUMOylating enzyme SENP3 in DS. There were also increased levels of SUMO-1 conjugated proteins in DS, but not in AD tissue. While these results do not exclude roles for SUMOylation in AD, they demonstrate clear differences in the profile of SUMOylation and in the expression of deSUMOylating enzymes between AD and DS brain.