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@ARTICLE{McDade:163359,
      author       = {McDade, Eric and Voytyuk, Iryna and Aisen, Paul and
                      Bateman, Randall J and Carrillo, Maria C and De Strooper,
                      Bart and Haass, Christian and Reiman, Eric M and Sperling,
                      Reisa and Tariot, Pierre N and Yan, Riqiang and Masters,
                      Colin L and Vassar, Robert and Lichtenthaler, Stefan F},
      title        = {{T}he case for low-level {BACE}1 inhibition for the
                      prevention of {A}lzheimer disease.},
      journal      = {Nature reviews / Neurology},
      volume       = {17},
      number       = {11},
      issn         = {1759-4766},
      address      = {London},
      publisher    = {Macmillan Publishers Limited, part of Springer Nature},
      reportid     = {DZNE-2022-00122},
      pages        = {703 - 714},
      year         = {2021},
      abstract     = {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-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.},
      subtyp        = {Review Article},
      keywords     = {Aged / Aged, 80 and over / Alzheimer Disease: prevention
                      $\&$ control / Amyloid Precursor Protein Secretases:
                      antagonists $\&$ inhibitors / Amyloid Precursor Protein
                      Secretases: genetics / Amyloid beta-Protein Precursor:
                      metabolism / Aspartic Acid Endopeptidases: antagonists $\&$
                      inhibitors / Aspartic Acid Endopeptidases: genetics /
                      Clinical Trials, Phase II as Topic / Clinical Trials, Phase
                      III as Topic / Enzyme Inhibitors: therapeutic use / Female /
                      Humans / Male / Middle Aged / Plaque, Amyloid: prevention
                      $\&$ control / Research Design / APP protein, human (NLM
                      Chemicals) / Amyloid beta-Protein Precursor (NLM Chemicals)
                      / Enzyme Inhibitors (NLM Chemicals) / Amyloid Precursor
                      Protein Secretases (NLM Chemicals) / Aspartic Acid
                      Endopeptidases (NLM Chemicals) / BACE1 protein, human (NLM
                      Chemicals)},
      cin          = {AG Haass / AG Lichtenthaler},
      ddc          = {610},
      cid          = {I:(DE-2719)1110007 / I:(DE-2719)1110006},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34548654},
      doi          = {10.1038/s41582-021-00545-1},
      url          = {https://pub.dzne.de/record/163359},
}