The case for low-level BACE1 inhibition for the prevention of Alzheimer disease

McDade, Eric; Voytyuk, Iryna; Aisen, Paul; Bateman, Randall J.; Carrillo, Maria C.; De Strooper, Bart; Haass, Christian; Reiman, Eric M.; Sperling, Reisa; Tariot, Pierre N.; Yan, Riqiang; Masters, Colin L.; Vassar, Robert und Lichtenthaler, Stefan E. (2021): The case for low-level BACE1 inhibition for the prevention of Alzheimer disease. In: Nature Reviews Neurology, Bd. 17, Nr. 11: S. 703-714

Abstract

To date, all phase III trials of beta-site amyloid precursor protein (APP)-cleaving enzyme (BACE) inhibitors for Alzheimer disease were either discontinued or produced negative results. Here the authors present their opinion that BACE inhibitors still hold promise as a preventative therapy for Alzheimer disease and outline a series of experiments to inform future trials. Alzheimer disease (AD) is the most common cause of dementia in older individuals (>65 years) and has a long presymptomatic phase. Preventive therapies for AD are not yet available, and potential disease-modifying therapies targeting amyloid-beta plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1;also known as beta-secretase 1) reduce the production of amyloid-beta peptide and are among the most advanced drug candidates for AD. However, to date all phase II and phase III clinical trials of BACE inhibitors were either concluded without benefit or discontinued owing to futility or the occurrence of adverse effects. Adverse effects included early, mild cognitive impairment that was associated with all but one inhibitor;preliminary results suggest that the cognitive effects are non-progressive and reversible. These discontinuations have raised questions regarding the suitability of BACE1 as a drug target for AD. In this Perspective, we discuss the status of BACE inhibitors and suggest ways in which the results of the discontinued trials can inform the development of future clinical trials of BACE inhibitors and related secretase modulators as preventative therapies. We also propose a series of experiments that should be performed to inform 'go-no-go' decisions in future trials with BACE inhibitors and consider the possibility that low levels of BACE1 inhibition could avoid adverse effects while achieving efficacy for AD prevention.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1759-4758
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198