Genetic and cardiometabolic contributions to cognitive, structural brain and biomarker phenotypes

Tank, Rachana (2022) Genetic and cardiometabolic contributions to cognitive, structural brain and biomarker phenotypes. PhD thesis, University of Glasgow.

Abstract

The number of individuals experiencing abnormal cognitive ageing is rapidly increasing, which can only in part be explained by an ageing population. Prevention of considerable cognitive decline is complicated by its heterogeneity and numerous risk factors. The most significant contributions to brain health and cognitive decline outside of age are higher genetic risk and poor cardiometabolic health. There are gaps in the literature and understanding regarding the extent to which common genetic or cardiometabolic conditions contribute to and interact with one another to influence brain health. Therefore, the overall aim of this PhD project is to explore genetic and cardiometabolic risks in relation to structural brain MRI measures, cognitive assessments, and blood biomarkers.

This thesis used large-scale secondary data from the UK Biobank in which several analyses investigating associations between cardiometabolic conditions, genetic risks, cognition, and brain MRI data are the largest to date. The use of the UK Biobank cohort also allowed for controlling of confounders that have not been considered or accounted for in previous studies. The primary focus of this thesis was on genetic and cardiometabolic contributions to cognition and brain MRI. The main objectives were: (1) Contribute to the understanding of cardiovascular to brain health and (2) Determine the role of genetic risk factors on the brain and physical health in healthy adults.

When examining multimorbidity, there were no clear trends between cardiometabolic groups and brain MRI metrics. However, this may have been due to a healthy selection bias in which those with multimorbidity were healthy enough for MRI assessments. When examining genetically elevated risk of cardiovascular disease (CVD) indexed by lipoprotein A (), we found associations with mean diffusivity and fractional anisotropy, suggesting a potential role of LpA in brain ageing. However, we found discrepancies between genetically elevated LpA and blood LpA, which should be further investigated.

When calculating genetic risk scores for Alzheimer’s disease (AD) in healthy midlife adults, we found evidence for potential early ageing pathology within subfields of the hippocampus prior to significant cognitive impairments. We also found that this elevated genetic risk for AD was associated with elevated cystatin c. Elevated genetic risk of AD also showed significant sex differences in biomarker analyses. Creatinine and oestradiol were significantly associated with an elevated risk of Alzheimer’s in women but not men. These findings support routine stratification in exploratory research.

This thesis emphasises the importance of epidemiological research that considers cardiometabolic, lifestyle and genetic risk factors together in the context of cognitive health. There is scope to build on this work in omics and cohort studies.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: R Medicine > R Medicine (General); R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Public Health
• Supervisor's Name: Lyall, Dr. Donald M., Flegal, Dr. Kristin E. and Cavanagh, Prof. Jonathan
• Date of Award: 2022
• Depositing User: Theses Team
• Unique ID: glathesis:2022-83028
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 08 Jul 2022 09:20
• Last Modified: 08 Jul 2022 09:24
• Thesis DOI: 10.5525/gla.thesis.83028
• URI: https://theses.gla.ac.uk/id/eprint/83028