Subsequent cleavage of C99 by γ-secretase/presenilin in the late endolysosomal compartments generates a cytoplasmic C-terminal fragment as well as small Aβ40 or Aβ42 peptides, which are the primary constituent of amyloid plaques, the pathological hallmark of AD (Masters et al., 1985; Sisodia, 1992; Takahashi et al., 2002; Vieira et al., 2010; Glenner and Wong, 2012; Rajendran and Annaert, 2012; van der Kant and Goldstein, 2015). Here, APP is linked to Alzheimer disease.