Investigating the role of APOE-ε4, a risk gene for Alzheimer's disease, on functional brain networks using magnetoencephalography

Alzheimer's disease (AD) is developing into the single greatest healthcare challenge in the coming decades. The development of early and effective treatments that can prevent the pathological damage responsible for AD-related dementia is of utmost priority for healthcare authorities. The role of the APOE-ε4 genotype, which has been shown to increase an individual's risk of developing AD, is of central interest to this goal. Understanding the mechanism by which possession of this gene modulates brain function, leading to a predisposition towards AD is an active area of research. Functional connectivity (FC) is an excellent candidate for linking APOE-related differences in brain function to sites of AD pathology. Magnetoencephalography (MEG) is a neuroimaging tool that can provide a unique insight into the electrophysiology underpinning resting-state networks (RSNs) - whose dysfunction is postulated to lead to a predisposition to AD. This thesis presents a range of methods for measuring functional connectivity in MEG data. We first develop a set of novel adaptations for preprocessing MEG data and performing source reconstruction using a beamformer (chapter 3). We then develop a range of analyses for measuring FC through correlations in the slow envelope oscillations of band-limited source-space MEG data (chapter 4). We investigate the optimum time scales for detecting FC. We then develop methods for extracting single networks (using seed-based correlation) and multiple networks (using ICA). We proceed to develop a group-statistical framework for detecting spatial differences in RSNs and present a preliminary finding for APOE-genotype-dependent differences in RSNs (chapter 5). We also develop a statistical framework for quantifying task-locked temporal differences in functional networks during task-positive experiments (chapter 6). Finally, we demonstrate a data-driven parcellation and network analysis pipeline that includes a novel correction for signal leakage between parcels. We use this framework to show evidence of stationary cross-frequency FC (chapter 7).This thesis is not currently available in ORA