Ultra-sensitive Mapping of Cell-free DNA-derived Methylomes Reveals Brain-specific Epigenetic Alterations Implicated in Alzheimer Disease

DNA cytosine modifications play a crucial role in gene regulation that underlies the pathogenesis of complex diseases such as Alzheimer disease (AD). Using LABS (Linear Amplification-based Bisulfite Sequencing), an ultra-sensitive linear amplification-based low-input whole-genome methylation profiling method, we demonstrated the feasibility of detecting altered methylation features in serum-derived cell-free DNA (cfDNA) between a set of age- and sex-matched pathologically-defined participants with AD and non-AD controls, from the Rush Memory and Aging Project. These blood methylation changes were further linked to brain-specific epigenetic alterations implicated in AD. These findings support cfDNA methylome profiling as a promising non-invasive tool for AD biomarker discovery and research.