PSEN1 and familial Alzheimer disease: With a phenotypic effect opposite to that of the PSEN1 mutations leading to early-onset fAD, which drives an accumulation of longer Aβ peptides due to impaired carboxypeptidase cleavage efficiency of γ-secretase (Chavez-Gutierrez et al., 2012), the promise of GSMs lies in their ability to reduce the accumulation of toxic longer forms of Aβ while preserving γ-secretase cleavage of its other substrates.