Modulation of brain olfactory (OR) and taste receptors (TASR) expression was recently reported in neurological diseases. We explored the possible expression and regulation of selected OR and TASR genes in human orbitofrontal cortex of sporadic Alzheimer’s disease (AD) and found that these are expressed and markedly downregulated at early stages. The expression pattern did not follow disease progression suggesting regulation through epigenetic mechanisms. We found an increase of global H3K9me3 levels and substantial enrichment of this repressive signature at ORs and TAS2Rs proximal promoter at early stages, ultimately lost at advanced stages. By mass spectrometry-based proteomic and further validation, we found that H3K9me3 interacts with MeCP2 at early stages and that this protein is increased in sporadic AD. Findings suggest MeCP2 might be implicated in OR and TAS2R genes expression regulation through interaction with H3K9me3, and as an early event, it may uncover a novel etiopathogenetic mechanism of sporadic AD.