Some of the phenotypes observed in first-generation AD models can also be critically reconsidered in light of the ‘presenilin hypothesis of AD’ as the increased workload of PSENs to metabolize overexpressed APP may divert the enzyme from the cleavage activity of the many other physiologically relevant substrates required for neuronal functioning (Haapasalo and Kovacs, 2011). The gene discussed is APP; the disease is Alzheimer disease.