The introduction of the amyloid hypothesis, which identifies amyloid as the primary target for treating Alzheimer’s disease (AD), was a watershed in the field of AD research. Treatment approaches have since focused on how amyloid might be manipulated. In fact, there are challenges to amyloid manipulation. First, removal of amyloid has shown minimal clinical effects. Second, some data indicate that secretase modulation shows hints of stimulating feedback systems, which cause concern over how to effectively manipulate amyloid. Third, side-effect profiles of the direct manipulation of amyloid are not currently optimal. Finally, evidence suggests that cell and synapse loss may be better markers of dementia and its severity. Alternative approaches to direct manipulation of amyloid include antioxidant mechanisms for prevention, anti-inflammatory mechanisms for neuroprotection, manipulation of metabolic risks, modification of tau accumulation, and neuroregeneration.

These alternative mechanisms of action provide support for a wide range of potential agents for clinical trials. The exact connection between mechanism of action and clinical outcomes is not well defined, but typically trial designs using these mechanisms attempt to measure affects on disease progression, often with longer studies that include established clinical outcomes accompanied by putative biomarkers of disease. One trend that has provided much information has been to examine the effects of these drugs in subjects at risk for AD, thereby expanding the intervention to prevention of disease. These studies include both secondary prevention studies, for example deferring onset in those with prodromal disease such as mild cognitive impairment (MCI), and primary prevention directed at those with no specific signs or symptoms.