In summary, our data implicate a role for altered γ-secretase activity during aging in the development of sporadic AD and neurodegeneration; aged mice exhibit altered specificity for Aβ40 and Aβ42 production and decreased Notch1 processing, both of which are reminiscent of certain PS FAD mutations that result in the development of early onset AD. Here, PSEN1 is linked to Alzheimer disease.