Old and new acetylcholinesterase inhibitors for Alzheimer’s disease

ABSTRACT

Introduction: To date, pharmacological treatment of Alzheimer’s disease (AD) includes Acetylcholinesterase Inhibitors (AChEIs) for mild-to-moderate AD, and memantine for moderate-to-severe AD. AChEIs reversibly inhibit acetylcholinesterase (AChE), thus increasing the availability of acetylcholine in cholinergic synapses, enhancing cholinergic transmission. These drugs provide symptomatic short-term benefits, without clearly counteracting the progression of the disease.

Areas covered: On the wake of successful clinical trials which lead to the marketing of AChEIs donepezil, rivastigmine and galantamine, many compounds with AChEI properties have been developed and tested mainly in Phase I-II clinical trials in the last twenty years. Here, we review clinical trials initiated and interrupted, and those ongoing so far.

Expert opinion: Despite many clinical trials with novel AChEIs have been carried out after the registration of those currently used to treat mild to moderate AD, none so far has been successful in a Phase III trial and marketed. Alzheimer’s disease is a complex multifactorial disorder, therefore therapy should likely address not only the cholinergic system but also additional neurotransmitters. Moreover, such treatments should be started in very mild phases of the disease, and preventive strategies addressed in elderly people.

KEYWORDS:

• Acetylcholinesterase inhibitors (AChEI)
• Alzheimer’s disease (AD)
• clinical trial

Article highlights

• Current pharmacological treatment of Alzheimer’s disease (AD) includes Acetylcholinesterase Inhibitors (AChEIs) for mild-to-moderate AD, and memantine for moderate-to-severe AD.

• AChEIs provide symptomatic short-term benefits, without clearly counteracting the progression of the disease.

• Many compounds with AChEI properties have been developed and tested mainly in Phase I-II clinical trials in the last twenty years.

• Many of these AChEIs have not been successful in a Phase III trial and so far none of them has been marketed.

• AD is a complex multifactorial disorder, therefore therapy should likely address not only the cholinergic system but also additional neurotransmitters.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

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