Functional connectivity in cognitively healthy young and middle-aged adults with genetic risk factors for neurodegenerative forms of dementia

The recent developments in neuroimaging suggest functional connectivity could be used as a potential biomarker in neurodegenerative disorders, such as Alzheimer’s Disease (AD). Investigating brain function of cognitively healthy individuals with risk factors for AD is, therefore, crucial in vulnerability monitoring that can inform clinical trial design, healthcare resources allocation, and lead to early identification and prevention. The aim of this PhD project is to discover the early changes in functional connectivity in individuals with an increased risk of neurodegenerative dementia but before any clinical symptoms occur. This project explores the link between four major genetic risk factors, namely APOE, MAPT, CD33, and CLU, and functional connectivity in cognitively healthy young and middle-aged adults. First, the thesis summarises the state-of-the-art of relevant functional connectivity research. Next, the thesis utilises the PREVENT-Dementia cohorts of 504 UK and Ireland based middle-aged individuals (aged 40-60 years) and 129 Chinese Han college students (aged 17-22 years). The participants are dichotomised into risk carriers and non-carriers. Where possible, a dose-dependent effect is studied. Multiple large-scale networks are explored by using Independent Component Analysis and Graph Theory. Several other analyses are performed including the relationship between connectivity, genotype, and cognition; the impact of using different methodologies; the impact of the APOEe4 effect on other genes; and the dose-dependent effect on functional connectivity. The main results show that all four genes influence functional connectivity in young adulthood and in middle-age but in different ways across multiple networks and in the areas that are typically affected by AD pathology in patients with dementia. These results support the notion of the genetics-related vulnerabilities in brain functional networks in young adulthood and middle-age. This project underlines the need for thorough understanding of the lifelong impact of genetic risk and resilience factors of AD on brain network organisation and dynamics.