Genetic screening in Alzheimer's disease (AD) has identified only a handful of genes that are mutated in the disorder. Thus, for a very large proportion of patients, the biology of their disease is poorly understood. Epigenetic alterations may provide an explanation in these cases. Using DNA methylation profiles of human hippocampus from controls and patients, we have identified the presence of promoter hypermethylation of the dual-specificity phosphatase 22 (DUSP22) gene in AD. DUSP22 is a likely candidate gene for involvement in the pathogenesis of the disorder since, as we demonstrate here, it inhibits PKA activity and thereby determines TAU phosphorylation status and CREB signaling.