Alzheimer’s disease (AD) is a devastating syndrome that accounts for 60–70% of all dementia cases, putting an enormous burden on global healthcare and economy. Unfortunately, there is no cure for AD, and the currently approved drugs are limited in their effects. Given the various pathological mechanisms behind AD, the “one-target, one-drug” paradigm for drug design became obsolete, and a new paradigm, polypharmacology, emerged. Consequently, a greater focus has been put towards multi-target directed ligands (MTDLs), as these can regulate several targets operating in the disease network. Parallel to that, cholinesterase inhibitors have regained popularity after decades of being considered only symptomatic agents with no disease-modifying properties. In this review, the current AD hypotheses and therapeutic targets, the concept of polypharmacology in AD pathology and the importance of cholinesterases in the pathogenesis and biochemical processes of AD are discussed, with a final overview of the current development in cholinesterase-based MTDLs.
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