[Molecular pathogenesis and development of disease-modifying drugs for Alzheimer's disease]

More than a decade after the approval of donepezil in Japan, three drugs (galantamine, rivastigmine, and memantin) were approved for Alzheimer's disease in 2011, which certainly widened the choice of drugs for Alzheimer's patients. Patients, however, show a steady decline of the cognitive function under treatment with choline esterase inhibitors or NMDA antagonists. Disease-modifying drugs to slow down or suppress the pathological process of the disease are highly anticipated. The development of disease-modifying drugs, however, has been facing a big problem over the last 20 years. Many compounds, including gamma-secretase inhibitors, gamma-secretase modulators, and BACE1 inhibitors, all failed to produce good results in clinical trials. Considering this situation, there is pessimism concerning the development of disease-modifying drugs under the present system of clinical trials. The negative results of clinical trials of immunotherapy for Alzheimer's disease have been disclosed in last summer. A new style of clinical trial of disease-modifying drugs for Alzheimer's disease is proposed and discussed, in which the reduction of the conversion rate from MCI to dementia, or even from the preclinical stage to MCI, could be used as the primary outcome of the clinical trials.