Cognitive deficits in human ApoE4 knock-in mice: A systematic review and meta-analysis

• Published in: Behavioural brain research 2024-08, Vol.471, p.115123, Article 115123
• Main Authors: van Heuvelen, Marieke J.G., van der Lei, Mathijs B., Alferink, Pien M., Roemers, Peter, van der Zee, Eddy A.
• Format: Article
• Language: English
• Subjects: Animals; Apolipoprotein; Apolipoprotein E3 - genetics; Apolipoprotein E4 - genetics; Cognition; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - physiopathology; Disease Models, Animal; Fear conditioning; Gene Knock-In Techniques; Genotype; Humans; Learning; Mice; Mice, Transgenic; Morris water maze; Novel location; Novel object; Rodent
• ISSN: 0166-4328; 1872-7549; 1872-7549
• DOI: 10.1016/j.bbr.2024.115123

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. •ApoE4 knock-in mice show cognitive deficits in several behavioral learning tasks•Reduced performance of ApoE4 mice in these cognitive tasks is not systematically related to sex or age.•The functional consequences of ApoE4 in otherwise healthy conditions are mild in ApoE4 knock-in mice•Swim patterns of the ApoE4 vs ApoE3 mice should be included in the analysis of the MWM protocol•ApoE4 knock-in mice are a suitable model to study the impact of the ApoE4 allele on