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The amyloid cascade hypothesis for Alzheimers disease: an appraisal for the development of therapeutics
Eric Karran*, Marc Mercken* and Bart De Strooper
Abstract | The amyloid cascade hypothesis, which posits that the deposition of the amyloid- peptide in the brain is a central event in Alzheimers disease pathology, has dominated research for the past twenty years. Several therapeutics that were purported to reduce amyloid- production or aggregation have failed in PhaseIII clinical testing, and many others are in various stages of development. Therefore, it is timely to review the science underpinning the amyloid cascade hypothesis, consider what type of clinical trials will constitute a valid test of this hypothesis and explore whether amyloid--directed therapeutics will provide the medicines that are urgently needed by society for treating this devastating disease.
The amyloid cascade hypothesis for Alzheimers disease (AD) (FIG.1) has been very influential in the research conducted in academia and the pharmaceutical industry. This hypothesis synthesizes histopathological and genetic information, and posits that the deposition of the amyloid- peptide in the brain parenchyma initiates a sequence of events that ultimately lead to AD dementia.
However, all of the amyloid--centric approaches that reached PhaseIII clinical trials have failed; tramiprosate, tarenflurbil and semagacestat have now been discontinued. The preclinical data and the clinical biomarker data for tramiprosate and tarenflurbil were not strong1,
but the failure of semagacestat a well-characterized -secretase inhibitor (GSI) was of particular note. Semagacestat was being evaluated in two PhaseIII trials, the Interrupting Alzheimers Dementia by Evaluating Treatment of Amyloid Pathology (IDENTITY) trial (http://www.clinicaltrials.gov/
Web End =ClinicalTrials.gov identifier: NCT00594568) and the IDENTITY-2 trial (ClinicalTrials.gov identifier: NTC00762411). This compound reduced amyloid- deposition in the PDAPP transgenic mouse (which over-expresses a mutated human amyloid precursor protein (APP)) after 5months of dosing2 and also showed a statistically significant reduction in newly synthesized amyloid- in human volunteers using stable isotope-linked kinetic (SILK) technology3. In fact, GSIs such as semagacestat have a very complex mode of action. This class of compounds is able to inhibit the production of amyloid- at high concentrations of the substrate and compound, but stimulates -secretase at lower concentrations of substrate and compound4.
Interestingly, an interim analysis from the PhaseIII trials demonstrated that patients who were treated with semagacestat displayed an increased deterioration in...