These studies lay the groundwork for the formulation of the “Ca2+ overload” hypothesis for AD that sustains that FAD-linked PS mutations, by increasing ER Ca2+ content, cause excessive Ca2+ release in the cytosol, altering APP processing, increasing neuronal sensitization to Aβ and producing cytotoxic stimuli that eventually lead to a Ca2+-dependent cell death [130]. The gene discussed is APP; the disease is Alzheimer disease.