PSEN1 and Alzheimer disease: It was initially established that mutations in FAD-associated PS1 and PS2 increase the ratio of Aβ42 to Aβ40 both in vivo and in vitro as well as in AD patients [6–9], although recent studies indicate that the increase in Aβ42 levels relative to Aβ40 may not be a universal phenotype associated with presenilin FADs [10].