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Exploring brain structure and blood metabolic profiles using Alzheimer's pathway specific polygenic risk scores

Harrison, Judith 2021. Exploring brain structure and blood metabolic profiles using Alzheimer's pathway specific polygenic risk scores. PhD Thesis, Cardiff University.
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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects older people. It is common, affecting around one in ten people over 65 years old. In addition to the autosomal dominant AD genes and Apolipoprotein E (APOE), genome wide association studies (GWAS) have identified a number of small risk loci. These can be combined into polygenic risk scores (PRS) which can predict AD relatively accurately and are associated with a number of neurodegeneration phenotypes. Pathway analyses of GWAS data have implicated a number of biological processes, including the immune response and lipid metabolism. How AD pathway specific genetic burden manifests in brain structure or serum metabolic profiles is not well understood. In this thesis, volumetric and diffusion MRI and serum lipid and inflammatory markers were used to investigate manifestations of AD polygenic risk in two large population cohorts. Specifically, these analyses sought to determine 1) whether AD polygenic risk scores were associated with neuroimaging and blood marker phenotypes linked to neurodegeneration in younger and older adult cohorts; and 2) whether PRS informed by disease pathways were associated with different patterns of alteration in brain structure, serum lipids or inflammatory markers. The relationships between PRS and phenotypes were explored using linear regression. There were significant associations between pathway specific PRS, grey matter volumes and white matter microstructure. Although some of these attenuated when the APOE region was excluded from the score, some were maintained, in particular cortical thickness in mature adults, which appeared to be independent of APOE. Increased pathway specific polygenic risk for AD was also associated with serum markers such as increased blood lipids, particularly low density lipoprotein (LDL) cholesterol and total cholesterol, and decreased C-Reactive Protein (CRP). However, these effects seemed to be driven by the APOE locus. Further longitudinal studies, combining advanced MRI techniques with cerebrospinal fluid and neuroradiology biomarkers, will be required to confirm these findings and assess their biological significance.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Psychology
Subjects: B Philosophy. Psychology. Religion > BF Psychology
Funders: Wellcome Trust
Date of First Compliant Deposit: 30 March 2021
Date of Acceptance: 30 March 2021
Last Modified: 01 Apr 2021 11:01

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