Identifying DNA Methylation Signatures in Alzheimer's Disease Blood

Abstract

Alzheimer’s disease is a complex, multifaceted disorder, which is estimated to affect over thirty six million people worldwide and is characterised by progressive neurodegeneration and cognitive decline. As the numerous genomic susceptibility loci that have been identified for the most common, sporadic form of Alzheimer’s disease do not fully account for the disease risk, epigenetic and environmental factors have been suggested to be involved in the aetiology and development of Alzheimer’s disease. Epigenetics, of which DNA methylation is perhaps the most studied mechanism, refers to transient, heritable changes in gene expression without the underlying genotype being altered. A growing number of epigenome-wide association studies have demonstrated robust differential DNA methylation in the brain of Alzheimer’s disease patients, though limited studies have been undertaken in blood. The aim of this thesis was to characterise blood DNA methylation profiles in Alzheimer’s disease, as well as individuals with mild cognitive impairment, who often progress to Alzheimer’s disease. Disease-associated profiles were characterised on autosomal chromosomes as well as sex chromosomes, and the effects and interactions of the Alzheimer’s disease risk factors sex and age were studied. The results from this thesis have provided novel insights into DNA methylation changes in blood related to Alzheimer’s disease, mild cognitive impairment, and future progression to Alzheimer’s disease. A region in the HOXB6 gene was found to be differentially methylated in Alzheimer’s disease, which presents an interesting target for future diagnostic biomarker studies. The results concerning the risk factors sex and age, and DNA methylation of the sex chromosomes, emphasise the importance of not only controlling for, but taking into account these factors.