DNA methylation variability in Alzheimer's disease.

DNA methylation plays a critical role in brain aging and Alzheimer's disease (AD). While prior studies have largely focused on testing mean DNA methylation, DNA methylation instability (quantified by DNA methylation variability) may also affect disease susceptibility. Using DNA methylation data collected by the Religious Orders Study and the Rush Memory and Aging Project, we identified 249 and 115 variably methylated probes (VMPs) associated with amyloid-β and neurofibrillary tangles, respectively. These VMPs clustered into 133 and 14 regions, respectively. Notably, we found that most of these VMPs did not overlap with differentially methylated probes, indicating that VMPs and differentially methylated probes may capture different sets of genes associated with AD pathology. Overall, our results demonstrated that DNA methylation instability affects AD neuropathology and highlights the importance of testing methylation variability in epigenetic research.