Although gene hunting has been carried out in Down Syndrome (DS) cells, information on expressional differences in DS brain is limited. We have recently described expressional differences in fetal DS brain but cannot assign these findings to "DS per" se or simply to "neurodegeneration". We therefore performed gene hunting in cerebellum of adult patients with DS and Alzheimer's disease (AD) neuropathology, AD and controls. The gene hunting method used was differential display and pools of the individual groups were examined to rule out allelic differences. Differential display revealed the absence of a band, identified by sequencing and gene bank work as matching the NADH3 gene (99.1% identity) in cerebellum of DS patients. Dot blots showed the presence of NADH3 signals in only two out of 7 DS patients. We show at the transcriptional level that a mitochondrial enzyme, the complex I, NADH3, is significantly downregulated in DS cerebellum. This extends previous work on deficiencies of the electron transport chain in platelets of patients with DS.