Abstract: The invention provides a method of preventing, delaying, or reversing the progression of Alzheimer's disease by administering an A?42 lowering agent to a mammal under conditions in which levels of A?42 are selectively reduced, levels of A?38 are increased, and levels of A?40 are unchanged. The invention provides methods and materials for developing and identifying A?42 lowering agents. In addition, the invention provides methods for identifying agents that increase the risk of developing, or hasten progression of, Alzheimer's disease. The invention also provides compositions of A?42 lowering agents and antioxidants, A?42 lowering agents and non-selective secretase inhibitors, as well as A?42 lowering agents and acetylcholinesterase inhibitors.