γ-secretase inhibitors for Alzheimer's disease: Balancing efficacy and toxicity

The amyloid hypothesis, which states that β-amyloid (Aβ) aggregates cause the onset and progression of Alzheimer's disease (AD), is a leading proposal to explain AD aetiology. Based on this hypothesis, compounds that inhibit γ-secretase, one of the enzymes responsible for forming Aβ, are potential therapeutics for AD. Preclinical studies clearly establish that γ-secretase inhibitors can reduce brain Aβ in rodent models. The initial investigation of the effects of a γ-secretase inhibitor on Aβ-induced cognitive deficits in transgenic mice showed that modest Aβ reductions (15-30%) are sufficient to reverse Aβ-induced cognitive deficits in Tg2576 mice. Extending these studies to other γ-secretase inhibitors and other models with Aβ-induced cognitive deficits will be important. Unfortunately, γ-secretase inhibitors also cause abnormalities in the gastrointestinal tract, thymus and spleen in rodents. These changes likely result from inhibition of Notch cleavage, a transmembrane receptor involved in regulating cell-fate decisions. Two recent studies in rodents suggest that Aβ reduction using γ-secretase inhibitors can be partially separated from Notch inhibition. Given the uncertain Aβ reduction target and the potential for mechanism-based toxicity, biomarkers for efficacy and toxicity would be helpful in clinical trials. The first report of γ-secretase inhibitors in clinical trials was recently published. In this study, LY-450139 reduced plasma Aβ, but not cerebrospinal fluid Aβ. Taken together, the results of studies to date suggest that γ-secretase inhibitors have the potential to address a large unmet medical need if the technical challenges can be overcome. © 2006 Adis Data Information BV. All rights reserved.