Alzheimer's disease: progress in the development of anti-amyloid disease-modifying therapies.

The amyloid hypothesis--the leading mechanistic theory of Alzheimer's disease--states that an imbalance in production or clearance of amyloid beta (Abeta) results in accumulation of Abeta and triggers a cascade of events leading to neurodegeneration and dementia. The number of persons with Alzheimer's disease is expected to triple by mid-century. If steps are not taken to delay the onset or slow the progression of Alzheimer's disease, the economic and personal tolls will be immense. Different classes of potentially disease-modifying treatments that interrupt early pathological events (ie, decreasing production or aggregation of Abeta or increasing its clearance) and potentially prevent downstream events are in phase II or III clinical studies. These include immunotherapies; secretase inhibitors; selective Abeta42-lowering agents; statins; anti-Abeta aggregation agents; peroxisome proliferator-activated receptor-gamma agonists; and others. Safety and serious adverse events have been a concern with immunotherapy and gamma-secretase inhibitors, though both continue in clinical trials. Anti-amyloid disease-modifying drugs that seem promising and have reached phase III clinical trials include those that selectively target Abeta42 production (eg, tarenflurbil), enhance the activity of alpha-secretase (eg, statins), and block Abeta aggregation (eg, transiposate).