Support for this so-called presenilin hypothesis was drawn from several experimental observations including the age-dependent neurodegeneration and memory impairments in conditional PSEN1/PSEN2 double knockout mice (47, 48), the drastically reduced enzyme activity of some PSEN1 mutants when assessed in overexpression or homozygous knock-in models (32, 40, 49, 50, 51), and the large size of γ-secretase complexes observed in early purification attempts consistent with oligomerization of its subunits (52, 53, 54). Here, PSEN1 is linked to memory impairment.