[Natural progression of Alzheimer's disease (AD): a perspective on possible therapies for advanced AD]

Patients with Alzheimer's disease (AD) show progressive deterioration in cognitive function without a spontaneous improvement in their course. Currently, acetylcholine esterase inhibitors (AchEIs) are generally used for treating AD and their beneficial effects have been confirmed for mild to moderate AD. Treatment options for patients with severe or advanced AD are limited; however, previous studies suggested that AchEIs, such as donepezil and galantamine, can provide some benefits for improving cognitive deficits even in patients with advanced AD. Furthermore, evidence of long-term benefits of donepezil treatment was reported by a recent study. Thus, AchEIs may have a wide spectrum of beneficial effects than we previously considered. Antiamyloid therapeutic strategies, including inhibition of the generation of amyloid beta-protein (A beta) and acceleration of A beta clearance, are likely to be highly effective for AD. A recent study of conditional transgenic mouse models of other neurodegenerative diseases suggested that a continuous influx of toxic aggregates of a mutant protein is required to maintain the pathological progression of the disease. Thus, although A beta generation and deposition are upstream of the amyloid cascade, it is likely that antiamyloid therapies can slow the natural progression of AD even in an advanced stage of the disease.