Consistent with this concept is the observation that compared to an age-matched healthy control group, individuals with Alzheimer's disease have reduced levels of the activated (i.e. phosphorylated) form of CREB [72]; calcium signaling to the cell nucleus is the key inducer of CREB phosphorylation on its activator site serine 133 [12]. This evidence concerns the gene CREB1 and early-onset autosomal dominant Alzheimer disease.