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Therapeutic intervention for Alzheimer's disease with γ-secretase inhibitors: still a viable option?

Introduction: Compounds that inhibit or modulate γ-secretase, the pivotal enzyme which generates β-amyloid (Aβ), are potential therapeutics for Alzheimer's disease (AD). Areas covered: This article briefly reviews the profile of γ-secretase inhibitors that have reached the clinic and discusses the clinical issues surrounding this new class of anti-AD compounds. Expert opinion: γ-Secretase inhibitors may cause significant toxicity in humans. Two large Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of detrimental cognitive and functional effects of the drug. These detrimental effects were mainly ascribed to the inhibition of Notch processing and the accumulation of the neurotoxic precursor of Aβ resulting from the block of the γ-secretase cleavage activity on amyloid precursor protein. New Notch-sparing γ-secretase inhibitors are being developed with the hope of overcoming the previous setbacks. It has also been argued that γ-secretase inhibitors should be used in the very early stages of the disease progression when neuronal loss is still limited. Thus, the inclusion of patients with mild-to-moderate AD in the semagacestat Phase III trials could also explain the negative outcome of these studies. Understanding the reasons for this failure may be important for future research on effective treatments for this devastating disease.