PSEN2 and Alzheimer disease: The concept that Aß accumulation is the major cause of AD has been supported by several lines of evidence: (i) deposition of Aß42, the most aggregable species of Aß with longer C terminus, is one of the earliest pathological changes observed in the brains of AD patients [3]; (ii) missense mutations of APP, as well as those of PSEN1 and PSEN2 encoding the catalytic subunit of γ-secretase, altogether cause familial AD [4–7], through a common mechanism of overproduction of Aß(1–42).