The gamma-secretase complex plays a role in Alzheimer's disease and cancer 
progression. The development of clinically useful inhibitors, however, is 
complicated by the role of the gamma-secretase complex in regulated 
intramembrane proteolysis of Notch and other essential proteins. Different 
gamma-secretase complexes containing different Presenilin or Aph1 protein 
subunits are present in various tissues. Here we show that these complexes have 
heterogeneous biochemical and physiological properties. Specific inactivation of 
the Aph1B gamma-secretase in a mouse Alzheimer's disease model led to 
improvements of Alzheimer's disease-relevant phenotypic features without any 
Notch-related side effects. The Aph1B complex contributes to total 
gamma-secretase activity in the human brain, and thus specific targeting of 
Aph1B-containing gamma-secretase complexes may help generate less toxic 
therapies for Alzheimer's disease.