
Thesis Format
Monograph
Degree
Master of Science
Program
Neuroscience
Supervisor
Prado, Marco A.M.
2nd Supervisor
Prado, Vania F.
Co-Supervisor
Abstract
Apolipoprotein-ε4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer’s Disease (AD). However, it has also been suggested to exhibit antagonistic pleiotropy, a phenomenon where a particular gene enhances fitness during some life stages but are detrimental in others. Research suggests that earlier in life, APOE4 carriers outperform non-carriers on tasks requiring executive function, but experience greater global cognitive decline with age. This study investigates the effect of APOE4 on cognition in humanized mouse models using the touchscreen cognition system. Our findings show that APOE4 mice exhibit better attentional performance compared to those carrying APOE3 in a murine model representing individuals at risk for AD. Furthermore, in mice representing individuals with early-onset AD, APOE4 impairs pattern separation and accelerates hippocampal amyloid deposition. These results offer insight into the dual impact of APOE4 on cognition, which will help guide future research on AD risk and progression.
Summary for Lay Audience
Alzheimer’s disease (AD) is an age-related brain disorder that causes gradual memory loss and cognitive decline. AD is characterized by the toxic buildup of beta-amyloid and tau proteins that damage brain cells. There are two main types of AD: early-onset (EOAD) and late-onset (LOAD). EOAD occurs before the age of 65 and is directly related to inherited genes. LOAD begins after 65 years and is influenced by a combination of less understood hereditary and environmental elements. To date, the most influential genetic risk factor for LOAD is a gene called apolipoprotein-E (APOE). ApoE regulates fat and cholesterol transport in the brain and bloodstream and exists in three forms (ApoE2, ApoE3, and ApoE4). Each variant affects AD development differently, particularly regarding the buildup of amyloid and tau. ApoE4 increases the risk of developing LOAD by up to 12 times and contributes to increased amyloid buildup. However, even though ApoE4 is linked to the development of AD, it has been hypothesized to be beneficial for some cognitive processes earlier in life such as attention and problem-solving skills.
This thesis explores how ApoE4 affects cognition at various stages of AD development. To achieve this, we used a newly generated mouse model carrying human versions of amyloid, tau, and ApoE genes, allowing for a more translatable representation of human disease development. Firstly, to assess how ApoE4 affects attention in mice with genetic risk factors for AD but not yet exhibiting the disease, we used the touchscreen cognition system to measure their attentional capacity. Our results show that ApoE4 mice have better attentional performance than those with ApoE3, with the effect being strongest in young female mice. Secondly, we used the same touchscreen system paired with an EOAD mouse model to examine the effects of ApoE4 on pattern separation, a memory process that distinguishes between similar but distinct experiences. Our results show that compared to ApoE3, mice carrying ApoE4 have impaired pattern separation and increased amyloid buildup in the hippocampus, the brain's memory center. Overall, these new mouse models have proved value tools in further understanding the role of ApoE in cognition and AD development.
Recommended Citation
Longmuir, Madison, "Investigating the Effect of APOE4 on Attention and Pattern Separation in New Mouse Models of Alzheimer’s Disease Risk" (2024). Electronic Thesis and Dissertation Repository. 10586.
https://ir.lib.uwo.ca/etd/10586
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