Cognitive effects of the BET protein inhibitor apabetalone: a prespecified Montreal Cognitive Assessment analysis nested in the BETonMACE randomized controlled trial
Author(s)
Type
Journal Article
Abstract
Background:
Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer’s disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic “readers” that may distort normal gene expression and contribute to chronic disorders.
Objective:
To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE).
Methods:
The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. 464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score≥26 (normal performance), MoCA score 25–22 (mild cognitive impairment), and MoCA score≤21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group.
Results:
Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of≤21 (p = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%).
Conclusion:
In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.
Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer’s disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic “readers” that may distort normal gene expression and contribute to chronic disorders.
Objective:
To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE).
Methods:
The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. 464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score≥26 (normal performance), MoCA score 25–22 (mild cognitive impairment), and MoCA score≤21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group.
Results:
Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of≤21 (p = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%).
Conclusion:
In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.
Editor(s)
Tousi, Babak
Date Issued
2021-10-04
Date Acceptance
2021-07-26
Citation
Journal of Alzheimer's Disease, 2021, 83 (4), pp.1703-1715
ISSN
1387-2877
Publisher
SAGE Publications
Start Page
1703
End Page
1715
Journal / Book Title
Journal of Alzheimer's Disease
Volume
83
Issue
4
Copyright Statement
© 2021– The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0)
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/34459400
PII: JAD210570
Subjects
Alzheimer's disease
ALZHEIMERS-DISEASE
apabetalone
ASSESSMENT MOCA
BET inhibitor
BIOMARKERS
BLOOD-BRAIN-BARRIER
BROMODOMAIN
clinical trial
DEMENTIA
epigenetics
INFLAMMATION
Life Sciences & Biomedicine
montreal cognitive assessment
Neurosciences
Neurosciences & Neurology
RISK
Science & Technology
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2021-08-24