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 (A beta) results in accumulation of A beta 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 A beta or increasing its clearance) and potentially prevent downstream events are in phase II or III clinical studies. These include immunotherapies; secretase inhibitors; selective A beta(42)-lowering agents; statins; anti-A beta 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 A beta(42) production (eg, tarenflurbil), enhance the activity of alpha-secretase (eg, statins), and block A beta aggregation (eg, transiposate).