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Aggregate Trends of Apolipoprotein E on Cognition in Transgenic Alzheimer's Disease Mice
Yassin Watson1, Brenae Nelson1, Jamie Hernandez Kluesner1
1Laboratory for Pathology Dynamics, Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, USA.
Background:
Apolipoprotein E (APOE) genotypes typically increase risk of amyloid-β deposition and onset of clinical Alzheimer's disease (AD). However, cognitive assessments in APOE transgenic AD mice have resulted in discord.
Objective:
Analysis of 31 peer-reviewed AD APOE mouse publications (n = 3,045 mice) uncovered aggregate trends between age, APOE genotype, gender, modulatory treatments, and cognition.
Methods:
T-tests with Bonferroni correction (significance = p < 0.002) compared age-normalized Morris water maze (MWM) escape latencies in wild type (WT), APOE2 knock-in (KI2), APOE3 knock-in (KI3), APOE4 knock-in (KI4), and APOE knock-out (KO) mice. Positive treatments (t+) to favorably modulate APOE to improve cognition, negative treatments (t-) to perturb etiology and diminish cognition, and untreated (t0) mice were compared. Machine learning with random forest modeling predicted MWM escape latency performance based on 12 features: mouse genotype (WT, KI2, KI3, KI4, KO), modulatory treatment (t+, t-, t0), mouse age, and mouse gender (male = g_m; female = g_f, mixed gender = g_mi).
Results:
KI3 mice performed significantly better in MWM, but KI4 and KO performed significantly worse than WT. KI2 performed similarly to WT. KI4 performed significantly worse compared to every other genotype. Positive treatments significantly improved cognition in WT, KI4, and KO compared to untreated. Interestingly, negative treatments in KI4 also significantly improved mean MWM escape latency. Random forest modeling resulted in the following feature importance for predicting superior MWM performance: [KI3, age, g_m, KI4, t0, t+, KO, WT, g_mi, t-, g_f, KI2] = [0.270, 0.094, 0.092, 0.088, 0.077, 0.074, 0.069, 0.061, 0.058, 0.054, 0.038, 0.023].
Conclusion:
APOE3, age, and male gender was most important for predicting superior mouse cognitive performance.
Insights
Apolipoprotein E3 (APOE3) genotype, advanced age, and male gender are key predictors of better cognitive function in mice. This contrasts with APOE4 and APOE knockout, which show impaired cognition.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Apolipoprotein E (APOE) genotypes are linked to Alzheimer's disease (AD) risk and amyloid-β deposition.
- Cognitive assessments in APOE transgenic AD mouse models have yielded inconsistent results.
Purpose of the Study:
- To analyze aggregate trends in APOE mouse models regarding age, genotype, gender, treatments, and cognitive performance.
- To identify key factors influencing cognitive outcomes in APOE transgenic mice.
Main Methods:
- Meta-analysis of 31 publications involving 3,045 APOE mouse models.
- Statistical comparison of Morris water maze (MWM) performance across genotypes (WT, KI2, KI3, KI4, KO) and conditions (treated, untreated).
- Machine learning (random forest) to predict MWM escape latency using 12 features.
Main Results:
- APOE3 knock-in (KI3) mice showed significantly better MWM performance; APOE4 (KI4) and knockout (KO) mice performed significantly worse than wild-type (WT).
- Positive modulatory treatments improved cognition in WT, KI4, and KO mice. Negative treatments unexpectedly improved KI4 performance.
- Random forest model identified APOE3 genotype, age, and male gender as most important for superior MWM performance.
Conclusions:
- APOE3 genotype, advanced age, and male gender are crucial for predicting enhanced cognitive performance in mice.
- These factors significantly influence cognitive outcomes in APOE mouse models of Alzheimer's disease.
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