TY  - JOUR
AU  - McDade, Eric
AU  - Voytyuk, Iryna
AU  - Aisen, Paul
AU  - Bateman, Randall J
AU  - Carrillo, Maria C
AU  - De Strooper, Bart
AU  - Haass, Christian
AU  - Reiman, Eric M
AU  - Sperling, Reisa
AU  - Tariot, Pierre N
AU  - Yan, Riqiang
AU  - Masters, Colin L
AU  - Vassar, Robert
AU  - Lichtenthaler, Stefan F
TI  - The case for low-level BACE1 inhibition for the prevention of Alzheimer disease.
JO  - Nature reviews / Neurology
VL  - 17
IS  - 11
SN  - 1759-4766
CY  - London
PB  - Macmillan Publishers Limited, part of Springer Nature
M1  - DZNE-2022-00122
SP  - 703 - 714
PY  - 2021
AB  - 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.
KW  - Aged
KW  - Aged, 80 and over
KW  - Alzheimer Disease: prevention & control
KW  - Amyloid Precursor Protein Secretases: antagonists & inhibitors
KW  - Amyloid Precursor Protein Secretases: genetics
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Aspartic Acid Endopeptidases: antagonists & inhibitors
KW  - Aspartic Acid Endopeptidases: genetics
KW  - Clinical Trials, Phase II as Topic
KW  - Clinical Trials, Phase III as Topic
KW  - Enzyme Inhibitors: therapeutic use
KW  - Female
KW  - Humans
KW  - Male
KW  - Middle Aged
KW  - Plaque, Amyloid: prevention & control
KW  - Research Design
KW  - APP protein, human (NLM Chemicals)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Enzyme Inhibitors (NLM Chemicals)
KW  - Amyloid Precursor Protein Secretases (NLM Chemicals)
KW  - Aspartic Acid Endopeptidases (NLM Chemicals)
KW  - BACE1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:34548654
DO  - DOI:10.1038/s41582-021-00545-1
UR  - https://pub.dzne.de/record/163359
ER  -