APP and Alzheimer disease: Since overproduction of Aβ42 in APP transgenic mice failed to induce neurodegeneration despite severe amyloidosis (Irizarry et al, 1997) and because many PS1 and PS2 FAD mutations strongly impair processing of γ‐secretase substrates such as Notch (Weggen & Beher, 2012), an alternative hypothesis for the disease mechanism of AD, the “presenilin hypothesis”, has been suggested, which states that AD is caused by a loss of essential presenilin functions (Shen & Kelleher, 2007).