Alzheimer’s disease

manhattan Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is characterized by progressive neuropathology and cognitive decline. We recently published a cross-tissue analysis of methylomic variation in AD using samples from multiple human post-mortem brain cohorts. We identified a differentially methylated region in the ankyrin 1 (ANK1) gene that was associated with neuropathology in the entorhinal cortex, a primary site of AD manifestation. This region was confirmed as being substantially hypermethylated in two other cortical regions (superior temporal gyrus and prefrontal cortex), but not in the cerebellum, a region largely protected from neurodegeneration in AD, or whole blood obtained pre-mortem from the same individuals. Neuropathology-associated ANK1 hypermethylation was subsequently confirmed in cortical samples from other independent brain cohorts. We are now characterising ANK1 in the brain to establish its functional role in neuropathology. Future work will look beyond DNA methylation and explore the role of DNA hydroxymethylation and various histone modifications in AD brain. Finally, in collaboration with other groups across the world, we are combining clinical, genetic and multi-omic data (GWAS, EWAS and transcriptomic data) in several thousand cases to undertake the first integrated meta-analysis of AD.

Biomarkers

BiomarkersAside from identifying novel mechanistic pathways involved in the etiology of AD, epigenomic analyses ultimately promise the development of novel translational clinical tools. At present a number of transcriptomic biomarkers for AD have already been developed, with specific clinical utility for the early diagnosis of the disease and monitoring drug response in clinical trials. We are currently exploring the utility of DNA methylation biomarkers as a robust and reliable alternative biomarker for early diagnosis of AD.

Mitochondrial epigenetics in AD

MitochondriaMitochondrial dysfunction is a consistent and increasingly reported feature of AD pathology in both the brain and white blood cells, although the molecular mechanism(s) mediating this phenomena are yet to be fully elucidated. Mitochondria are cylindrical organelles containing approximately 16.6 kb of DNA (mtDNA), which is separate to the nuclear genome and inherited in a maternal, non-Mendelian fashion. We are currently funded by Alzheimer’s Research UK to investigate whether mtDNA methylation differences may be involved in mediating the mitochondrial dysfunction associated with AD pathogenesis.