Peripheral DNA methylation of candidate Alzheimer’s disease risk genes and its associations with cognition, brain volume and amyloid-β burden

Alzheimer’s disease (AD) is a growing major public health issue, affecting millions of people worldwide. Genome-wide association studies (GWAS) have identified over 50 loci associated with late-onset AD risk. However, most disease-associated variants are located in noncoding regions of the genome, making it difficult to elucidate exactly how disease risk is affected. Variants within noncoding regions can modulate disease risk through mechanisms such as gene expression regulation, which can be regulated by DNA methylation, which has, in recent years, been implicated in dementia and AD. This study utilised data from two well-characterised longitudinal studies, the Australian Imaging, Biomarker and Lifestyle (AIBL) study ( n = 565) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI; n = 533), and aimed to investigate the association between peripheral blood DNA methylation at CpG sites located in previously implicated AD-risk genes and cognition, MRI volumetric measures and brain Aβ-amyloid (Aβ) burden. Analyses were undertaken across the preclinical to prodromal population as well as within subsets classified by clinical diagnosis and Aβ burden using two methods: all CpG sites within a candidate gene and a representative site from each gene region with the greatest variance (mean absolute deviation; MAD). We identified numerous associations in the AIBL cohort that remained significant after correction for the false discovery rate, although only one novel site was validated in the ADNI cohort. This was located within the gene body region of CR1 (cg00416522) and was associated with ventricle volume in cognitively unimpaired individuals with high brain Aβ burden. While this study’s results contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related traits, they suggest that there are limited associations of peripheral DNA methylation with cognitive and neuroimaging traits in the a priori AD-risk genes that were screened in this study. Future meta-analyses across studies with larger cohort sizes and phenotypically rich datasets will help to confirm this finding and potentially elucidate further associations, while unbiased approaches are warranted and may uncover novel peripheral DNA methylation associations.