[Strategy and perspectives for development of Alzheimer disease-modifying drugs]

Although there has been a much progress in the clarification of the pathophysiology of Alzheimer disease (AD) over the last two decades, bona fide drugs that suppress the emergence and progression of the disease are not available yet. Fortunately, in addition to donepezil, two other cholinesterase inhibitors, namely galantamine and rivastigmine, and an NMDA receptor antagonist, memantine, have recently been approved for the treatment of AD patients at mild to moderately severe and moderately severe to severe stages of the disease, respectively, in Japan. These drugs potentially improve symptoms of AD; however, their disease-modifying effects are limited. Thus, AD is still the largest unmet medical need in neurology. To develop disease-modifying drugs for AD, the molecular mechanisms underlying AD must be clarified. On the basis of the findings that amyloid pathology proceeds 10 to 15 years prior to the emergence of clinical symptoms, disease-modifying drugs, particularly anti-amyloid drugs should be administered much earlier than that in the case of current clinical trials. Attention should also be paid to AD-associated pathologic proteins other than amyloid beta-protein, e.g., tau, to control the progression of AD, because evidence is accumulating that tau is involved in the amyloid-dependent and-independent pathophysiology of AD.