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000163359 037__ $$aDZNE-2022-00122
000163359 041__ $$aEnglish
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000163359 1001_ $$0P:(DE-HGF)0$$aMcDade, Eric$$b0
000163359 245__ $$aThe case for low-level BACE1 inhibition for the prevention of Alzheimer disease.
000163359 260__ $$aLondon$$bMacmillan Publishers Limited, part of Springer Nature$$c2021
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000163359 520__ $$aAlzheimer 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-β plaques in symptomatic stages of AD have only just been approved in the United States. Small-molecule inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; also known as β-secretase 1) reduce the production of amyloid-β 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.
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000163359 650_7 $$2NLM Chemicals$$aAPP protein, human
000163359 650_7 $$2NLM Chemicals$$aAmyloid beta-Protein Precursor
000163359 650_7 $$2NLM Chemicals$$aEnzyme Inhibitors
000163359 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases
000163359 650_7 $$0EC 3.4.23.-$$2NLM Chemicals$$aAspartic Acid Endopeptidases
000163359 650_7 $$0EC 3.4.23.46$$2NLM Chemicals$$aBACE1 protein, human
000163359 650_2 $$2MeSH$$aAged
000163359 650_2 $$2MeSH$$aAged, 80 and over
000163359 650_2 $$2MeSH$$aAlzheimer Disease: prevention & control
000163359 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: antagonists & inhibitors
000163359 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: genetics
000163359 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: metabolism
000163359 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: antagonists & inhibitors
000163359 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: genetics
000163359 650_2 $$2MeSH$$aClinical Trials, Phase II as Topic
000163359 650_2 $$2MeSH$$aClinical Trials, Phase III as Topic
000163359 650_2 $$2MeSH$$aEnzyme Inhibitors: therapeutic use
000163359 650_2 $$2MeSH$$aFemale
000163359 650_2 $$2MeSH$$aHumans
000163359 650_2 $$2MeSH$$aMale
000163359 650_2 $$2MeSH$$aMiddle Aged
000163359 650_2 $$2MeSH$$aPlaque, Amyloid: prevention & control
000163359 650_2 $$2MeSH$$aResearch Design
000163359 7001_ $$aVoytyuk, Iryna$$b1
000163359 7001_ $$aAisen, Paul$$b2
000163359 7001_ $$0P:(DE-HGF)0$$aBateman, Randall J$$b3
000163359 7001_ $$0P:(DE-HGF)0$$aCarrillo, Maria C$$b4
000163359 7001_ $$aDe Strooper, Bart$$b5
000163359 7001_ $$0P:(DE-2719)2202037$$aHaass, Christian$$b6$$udzne
000163359 7001_ $$0P:(DE-HGF)0$$aReiman, Eric M$$b7
000163359 7001_ $$aSperling, Reisa$$b8
000163359 7001_ $$0P:(DE-HGF)0$$aTariot, Pierre N$$b9
000163359 7001_ $$aYan, Riqiang$$b10
000163359 7001_ $$aMasters, Colin L$$b11
000163359 7001_ $$aVassar, Robert$$b12
000163359 7001_ $$0P:(DE-2719)2181459$$aLichtenthaler, Stefan F$$b13$$eLast author$$udzne
000163359 773__ $$0PERI:(DE-600)2491518-X$$a10.1038/s41582-021-00545-1$$gVol. 17, no. 11, p. 703 - 714$$n11$$p703 - 714$$tNature reviews / Neurology$$v17$$x1759-4766$$y2021
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