Exploring sub-phenotype variation in Alzheimer’s disease

Katzourou, Ioanna 2022. Exploring sub-phenotype variation in Alzheimer’s disease. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

The main aim of this thesis is to explore the presence of distinct sub-phenotypes within Alzheimer’s disease (AD) and to attempt to identify genetic and environmental factors that may influence the occurrence of these sub-phenotypes. Firstly, the rate of cognitive decline in AD was selected as a phenotypic domain of interest and examined. Secondly, the cooccurrence of behavioural and psychological symptoms in AD was investigated. A large phenotypic and genetic database including diverse phenotypic information on 4,163 individuals was used in this thesis, hereby termed the Cardiff Genetic Resource for AD (CAGRAD). A subset of this dataset that had been assessed longitudinally was used to derive a metric of cognitive decline in AD using mixed effects linear modelling. The metric derived was then used in various genetic studies, including a candidate gene study, a genome-wide association study, a pathway analysis and a polygenic risk score (PRS) analysis. The results of these analyses were replicated in an independent dataset. No genetic variants were found to be associated with the metric of cognitive decline, with the findingssuggesting that the genetic risk for faster decline within AD is unrelated to the genetic background of AD. Subsequently, a principal component analysis of psychiatric symptoms of AD was performed to identify subphenotypes of co-occurring symptoms, which were then used in a PRS analysis, aiming to identify shared genetic architecture between them and common psychiatric conditions. Five psychiatric sub-phenotypes in AD were identified and were found to share genetic aetiology with psychiatric conditions. These results can help deconvolute the heterogeneity observed in AD symptomology and shed some light into aspects of AD that are often overlooked.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	11 October 2022
Last Modified:	10 Oct 2023 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/153282

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