Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Neuroscience

Supervisor

Dr Arthur Brown

2nd Supervisor

Dr Marco Prado

Co-Supervisor

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder, marked by cognitive decline influenced by genetic and environmental risk factors. The APOE4 allele, the strongest genetic risk factor for late-onset AD, provides cognitive benefits in young carriers but impairs cognition in older age. APOE4 also worsens outcomes following traumatic brain injury (TBI), an environmental AD risk factor, though long-term effects are less known. Using a humanized mouse model, we assessed long-term cognitive outcomes post-TBI. Our methods included: (i) knock-in mice expressing wildtype APP, tau, and APOE4 without mutations; (ii) a repetitive closed-head mild TBI model with translatable rotational forces; and (iii) a rodent touchscreen continuous performance task (CPT) akin to clinical CPTs. Results showed that APOE4 mice outperformed APOE3s in attention tasks only in females, but better attention was lost post-TBI. The attentional changes indicated that while APOE4 can confer benefits, it accelerates cognitive decline when combined with TBI and female sex.

Summary for Lay Audience

Alzheimer’s disease (AD) is an age-related brain disorder, associated with a gradual decline in mental functioning, especially in memory and attention. Many factors, including genetics and life experiences, can increase the risk of developing AD and accelerate its progression. The strongest genetic risk factor for late-onset AD is the Apolipoprotein E4 gene (APOE4), which plays a central role in pathological processes in AD, including protein aggregation and long-term inflammation. APOE4 has different effects on mental functioning across the lifespan, such that it confers benefits in mental functioning in young adults, especially in attention, but impairs mental abilities in older adults. Moreover, APOE4 interacts with other risk factors such as concussive brain injuries to further accelerate AD onset. Following mild brain injuries, those that carry the APOE4 gene experience worse recovery and poorer mental abilities short-term following injury; however, less is known about long-term changes in mental functioning.

To address this, we utilized a mouse model of APOE4 and brain injury while considering clinical relevance. First, as mouse AD-related proteins do not form the pathological aggregates as they do in humans, we inserted two human genes that allow aggregation of such proteins without any disease-causing mutations. Second, we modeled three brain injuries after rotational forces experienced during sport-related human concussive brain injuries. Specifically, as the rotational forces are shown to be more damaging to the brain, we scaled down such forces to a mouse brain, to produce similar damage. Lastly, we longitudinally measured attention using a task that is nearly identical to the test given to humans in clinics. We found that without any injuries, female mice with the APOE4 gene had better attention skills than those with a non-risk factor APOE3 gene. This benefit lasted as the mice got older. However, after the mice experienced brain injuries, the APOE4 mice lost the better attention. Moreover, this change was seen exclusively in female mice, with no impact on males. Taken together these results suggest that the APOE4 gene might not be a risk factor for poor cognition by itself, and may even be beneficial for women; however, in the presence of other risk factors such as brain injury, APOE4 can lead to an accelerated cognitive decline, especially for women.

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