Pharmacologists and Alzheimer disease therapy: to boldly go where no scientist has gone before

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment, inability to perform activities of daily living and mood changes. Acetylcholinesterase inhibitors or NMDA glutamate receptor antagonists are currently used for the treatment of AD, but only the former have weak beneficial effects on cognitive function.

The aim of this review is to provide an overview of the main pharmacological features of both current drugs and new compounds which are still under clinical development for the treatment of AD.

The discovery of new drugs acting at the early stage of AD could be considered as a 'medical need' and inhibitors of γ-secretase or monoclonal antibodies against Aβ seemed good options. However, inhibitors of γ-secretase, that is, tarenflurbil or semagacestat, were discontinued due to their lack of cognitive improvement or unacceptable side effects. A careful evaluation of the risk:benefit ratio should be considered for monoclonal antibodies since, by increasing the disaggregation of fibrillar amyloid-β-peptide (Aβ), they could increase the neurotoxicity of soluble Aβ oligomers. In conclusion, the discovery of new drugs efficacious in AD subjects is an ambitious goal, however, and one that will require close, active collaboration by pharmacologists, chemists and clinicians.