| Summary: | <p>Whilst advancing age is, on average, associated with declining cognitive abilities, the course of cognitive ageing is highly variable at the individual level. The overall aim of this thesis was to improve understanding of risk and protective factors associated with variability in cognitive ageing. I first explored the effect of Alzheimer’s risk gene ‘APOE’ on cognition in healthy adults, and by reviewing the extensive literature, I showed that APOE genotype can have diverse cognitive consequences via multiple neurobiological mechanisms, each with applications to distinct aspects of cognitive ageing and Alzheimer’s disease (AD). I also investigated subjective memory impairment (SMI), which like APOE is associated with increased AD risk, but is also commonly reported by healthy older adults. By presenting a clinical case of persistent SMI, and reviewing evidence for the long-term relevance of brain characteristics in SMI, I reported that MRI can detect early differences in brain structure that herald subsequent cognitive impairment, valuable in clinical settings to identify the most at-risk SMI cases.</p> <p>I also investigated protective factors that preserve cognitive ability in some older adults, particularly whether the brain supports this superior cognitive ageing in multiple ways, via some older adults maintaining more ‘youthful’ brains, and others harnessing additional functional resources to ‘adapt’ to the challenge of brain ageing. Using structural and functional brain metrics alone, I identified multiple patterns of brain ageing predicted to be associated with superior cognitive ageing, and compared cross-sectional and longitudinal cognitive performance, as well as multi-modal MRI metrics acquired at multiple time points between groups. Across these analyses, I found convergent evidence that maintenance of more ‘youthful’ brain structure and function is associated with prior and continued superior cognitive and brain outcomes, particularly in grey and white matter structure, so promotion of this brain profile should be a goal of interventions. High frontal resting- state connectivity in older adults with poorer brain structure was not associated with the predicted cognitive performance benefit, when compared to those with lower structural and functional brain characteristics. Overall, this thesis provides novel insights into risk and protective factors related to variability in cognitive ageing, upon which further use of sensitive cognitive and imaging measures, and unique populations such as the oldest-old, can expand to inform markers and interventions to maximise cognitive abilities in later life.</p>
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