Since γ‐secretase substrate accumulation is limited in single Aph1a or Aph1bc cKO Cre+ mice, and not associated with a neurodegenerative phenotype, further development of selective γ‐secretase inhibitors, and in particular drugs targeting the combination PSEN1/APH1B, might be considered for treatment of Alzheimer's disease. Here, APH1B is linked to Alzheimer disease.