RAPGEF4 and Alzheimer disease: Reduced Epac2 mRNA was shown in the frontal cortex and hippocampus regions of Alzheimer's brains.89 Considering the crucial role of Epac2 in synapse remodeling and dendrite morphology,90 decreases in Epac2 expression in the post-mortem brain of AD patients may result from loss of neurons and synapses in the late stage of AD.