Late-onset Alzheimer disease (LOAD) is the most frequent cause of dementia in elderly adults. However, the factors determining disease onset remain unclear. In the elderly, the activation and expression of the gene encoding RE-1 silencing transcription factor (REST) may be a determinant of neuroprotective mechanisms and good amyloidogenic pathway management. In the present study, the minimal promoter region of REST1 was genetically and epigenetically analyzed in blood samples from 21 subjects with LOAD and 20 cognitively healthy elderly subjects. Genomic DNA was isolated, treated with bisulfite and pyrosequenced, and gene expression was determined using real-time PCR. Notably, subjects with LOAD exhibited hypermethylation and significantly diminished expression of REST1 compared with healthy subjects (p = 0.001). In the LOAD group, the gene expression of CAT, SOD2 and GPX also showed a significant decrease and an increase in malondialdehyde. A docking analysis revealed that the first zinc finger protein Sp1 recognized and bound the methylated sequence in subjects with LOAD differently than the binding observed in control subjects. These results reveal that in patients with LOAD the methylation of specific sites in the promoter sequence of REST suppresses its expression and this could be regulating the decreased expression of CAT, SOD and GPX, besides interfering with the action of transcription factors as Sp1.