The disclosure of disease-related phenotypes in Epac1/2-/- mice, and the association with insulin secretion [25, 83] and diseases such as Alzheimer’s disease [84] and depression [85], has prompted considerable efforts to develop compounds that target either Epac1 or Epac2 without affecting PKA signaling [8, 64, 86]. Here, RAPGEF4 is linked to early-onset autosomal dominant Alzheimer disease.