Reconsideration of Anticholinesterase Therapeutic Strategies against Alzheimer's Disease.

Alzheimer's disease (AD) is well-known as a severe neurodegeneration disease involving complicated etiologies, and cholinesterase inhibition remain the prevailing mode of clinical intervention in AD management. Although most clinically applied cholinesterase inhibitors (ChEIs) achieve limited clinical outcomes, research on the central cholinergic system is still thriving. Recently, an impressive amount of knowledge regarding novel acetylcholinesterase functions, as well as the close association between the central cholinergic system and other key elements for AD pathogenesis, has accumulated, highlighting that this field still has great potential for future drug development. In contrast to the overwhelmingly disappointing clinical therapeutic effects of various disease-modifying drug candidates, interesting evidence has continued to emerge over the past 20 years from the wealth of preclinical and clinical data on the usage of ChEIs, indicating underestimated clinical benefits due to physician ambivalence, a lack of persistent treatment, and inappropriate medication times or doses. Here we pinpoint several topics fit for future attention, focusing on the updated cholinergic hypothesis, especially the pleiotropic relationships with key pathogenetic signaling pathways and functions in AD, as well as possible novel therapeutic strategies, including novel ChEIs and cholinesterase inhibition-based innovative multifunctional therapeutic candidates. We intend to strengthen the future value of the precise application of cholinergic drugs, especially novel ChEIs, as a cornerstone pharmacological approach to AD treatment, either alone or in combination with other targets, to relieve symptoms and to modify disease progression.