| Summary: | <p>The human apolipoprotein E (APOE) gene has three alleles (ε2, ε3 and ε4). Relative to the most common ε3 allele, ε4 is associated with a higher risk of developing sporadic late-onset Alzheimer’s disease (AD) whereas ε2 is believed to confer a protection to AD. Because of ε4's close association with cognitive decline, the majority of APOE-research has focused on this allele, with ε2 receiving little attention. This DPhil thesis used advanced multi-modal magnetic resonance imaging techniques in cognitively healthy young (20-40 years), middle-age (35-55 years) and older (60-85 years) adults to fulfil two objectives: (1) to present the first detailed examination of the effects of ε2 on brain structure and function across life, and (2) to study the early-life effects of APOE on cerebrovascular and neurochemical health, both of which are characteristically impaired in AD but have not been investigated in relation to APOE. We found that while APOE did not exert strong effects on brain structure or neurochemistry across the lifespan, there were significant allele-specific changes in brain function and vascular health. APOE’s effects on functional connectivity of the posterior cingulate cortex varied with age (connectivity in young adults: <em>ε4 &GT; (ε2 and ε3)</em>; older adults: <em>(ε2 and ε3) &GT; ε4)</em>. APOE ε2 carriers displayed an upward and ε4 carriers a declining trend in functional connectivity from young to older ages, with the middle-age range serving as a crossing point for the two opposing trajectories. Notably, similar increases in brain activity were observed within the hippocampus during a memory-encoding task in young ε4 carriers relative to non-carriers, suggesting a link between ε4 and early-life functional hyperactivity. We also found that young ε4 carriers had the worst and ε2 carriers the most robust measures of cerebrovascular reactivity (measured as the compensatory blood flow to the brain in response to breathing carbon dioxide, <em>i.e.</em> CO<sub>2</sub>-CVR). Early-life changes in cerebrovascular function may explain why ε4 carriers are more vulnerable to amyloid deposition and by contrast, why ε2 carriers remain relatively protected from AD-related neuropathology. Evidence suggests that impairments in CO<sub>2</sub>-CVR can be pharmacologically restored, making this measure a particularly useful preclinical marker of AD risk. Overall, this thesis provides valuable insights into the effects of APOE in the brain, and lends support to our growing understanding of AD as a vascular disorder.</p>
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