New evidence suggests upregulation of histone deactylase 2 (HDAC2) plays a central part in cognitive decline in Alzheimer disease (AD) through epigenetic modifications. Compared with controls, HDAC2 levels were significantly increased in hippocampal neurons of AD mice, and transcription of genes implicated in learning and memory was reduced. Knockdown of HDAC2 with short-hairpin RNA improved performance in learning and memory tasks. Moreover, in postmortem samples from patients with AD, HDAC2 levels were elevated in hippocampal area CA1 and the entorhinal cortex.