Investigating APOE DNA methylation in Alzheimer's disease and its relationship to APOE ε4 genotype
Date: 26 May 2020
University of Exeter
Masters by Research in Medical Studies
Alzheimer’s disease is a neurodegenerative condition that is the leading cause of dementia in the elderly, which affected close to 50 million people worldwide in 2017. The disease is characterised by the presence of amyloid beta plaques and neurofibrillary tangles of hyperphosphorylated tau protein in the brain. There are no disease-modifying ...
Alzheimer’s disease is a neurodegenerative condition that is the leading cause of dementia in the elderly, which affected close to 50 million people worldwide in 2017. The disease is characterised by the presence of amyloid beta plaques and neurofibrillary tangles of hyperphosphorylated tau protein in the brain. There are no disease-modifying treatments, largely because the mechanisms underlying disease and pathology are not understood. It is estimated that common genetic variants explain ~33% of disease incidence, although the mechanism behind their action is not clear. Polymorphisms in the APOE gene have been widely linked with AD, and the APOE ε4 variant is the greatest genetic risk factor for sporadic Alzheimer’s disease. We hypothesise that epigenetic differences, namely DNA methylation, in APOE may contribute to Alzheimer’s disease aetiology and that this may also be related to APOE genotype. In this thesis we have investigated DNA methylation in prefrontal cortex and temporal gyrus tissue form individuals with varying degrees of pathology or disease using data from the Illumina 450K methylation array. We identified pathology-associated hypomethylation of APOE in four probes that reside in a CpG island in the 3’ untranslated region. Using a large cohort of pre-natal and post-natal brain tissue samples from individuals with methylation and matched genotype data we showed that methylation of one site in this region seems to be driven by APOE ε4 genotype in pre-natal development, although this was not observed in post-natal samples. We did however identify another loci in this island that showed hypomethylation with age in post-natal samples. In the promoter at the 5’ end of the gene we observed three adjacent loci near the transcription start site and one loci in the gene body that were significantly hypomethylated with advancing age in Alzheimer’s disease samples. Overall APOE ε4 genotype had little effect on APOE DNA methylation in the context of Alzheimer’s disease. This project is the first large-scale study of APOE DNA methylation with respect to Alzheimer’s disease diagnosis and pathology, age and APOE genotype and highlights the need for further work in to the role of APOE DNA methylation in disease aetiology.
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