Cognitive deficits in human ApoE4 knock-in mice: A systematic review and meta-analysis
Marieke J G van Heuvelen1, Mathijs B van der Lei2, Pien M Alferink1
1Department of Human Movement Sciences, University of Groningen, University Medical Center Groningen, Groningen, A. Deusinglaan 1, Groningen 9713AV, the Netherlands.
Abstract:
Apolipoprotein-E4 (ApoE4) is an important genetic risk factor for Alzheimer's disease. The development of targeted-replacement human ApoE knock-in mice facilitates research into mechanisms by which ApoE4 affects the brain. We performed meta-analyses and meta-regression analyses to examine differences in cognitive performance between ApoE4 and ApoE3 mice. We included 61 studies in which at least one of the following tests was assessed: Morris Water Maze (MWM), novel object location (NL), novel object recognition (NO) and Fear Conditioning (FC) test. ApoE4 vs. ApoE3 mice performed significantly worse on the MWM (several outcomes, 0.17 ≤ g ≤ 0.60), NO (exploration, g=0.33; index, g=0.44) and FC (contextual, g=0.49). ApoE4 vs. ApoE3 differences were not systematically related to sex or age. We conclude that ApoE4 knock-in mice in a non-AD condition show some, but limited cognitive deficits, regardless of sex and age. These effects suggest an intrinsic vulnerability in ApoE4 mice that may become more pronounced under additional brain load, as seen in neurodegenerative diseases.
Insights
Apolipoprotein-E4 (ApoE4) knock-in mice show cognitive deficits in memory and learning tasks compared to ApoE3 mice. These findings suggest an inherent vulnerability in ApoE4 mice, potentially worsening under neurodegenerative conditions.
Area of Science:
- Neuroscience
- Genetics
- Cognitive Science
Background:
- Apolipoprotein-E4 (ApoE4) is a significant genetic risk factor for Alzheimer's disease (AD).
- Targeted-replacement human ApoE knock-in mouse models are crucial for studying ApoE4's brain effects.
- Understanding cognitive differences between ApoE4 and ApoE3 mice is vital for AD research.
Purpose of the Study:
- To conduct meta-analyses and meta-regression to compare cognitive performance between ApoE4 and ApoE3 mice.
- To identify specific cognitive domains affected by the ApoE4 genotype.
- To investigate the influence of sex and age on these cognitive differences.
Main Methods:
- Meta-analysis and meta-regression of 61 studies involving ApoE4 and ApoE3 knock-in mice.
- Inclusion of cognitive tests: Morris Water Maze (MWM), novel object location (NL), novel object recognition (NO), and Fear Conditioning (FC).
- Analysis of cognitive performance outcomes (standardized mean difference, g).
Main Results:
- ApoE4 mice exhibited significantly worse performance compared to ApoE3 mice in MWM, NO, and FC contextual tests.
- Effect sizes (g) ranged from 0.17 to 0.60 for MWM, 0.33 to 0.44 for NO, and 0.49 for FC.
- No systematic relationship was found between ApoE4 vs. ApoE3 cognitive differences and the sex or age of the mice.
Conclusions:
- ApoE4 knock-in mice display limited, but significant, cognitive deficits in non-Alzheimer's disease conditions.
- These deficits are observed irrespective of sex and age, indicating an intrinsic vulnerability.
- The findings suggest ApoE4 may predispose individuals to more pronounced cognitive decline under additional brain stress, such as in neurodegenerative diseases.
