A 5‐hydroxymethylation‐based clock derived from cell‐free DNA in blood reveals accelerated epigenetic aging in patients with Alzheimer’s disease

Abstract

AbstractBackgroundEnvironmental exposure and lifestyle factors can induce epigenetic aging acceleration that has been implicated in various complex diseases. Enabling technologies compatible with convenient biospecimens, e.g., 2‐3 mL of blood, will facilitate clinical application. Targeting 5‐hydroxymethylcytosines (5hmC), a stable and under‐investigated regulator in the human genome, may improve our understanding of epigenetic aging and its implications in Alzheimer’s disease (AD).MethodUsing our previously published genome‐wide 5hmC profiles derived from cell‐free DNA (cfDNA) in blood (∼1,200 healthy individuals [HEA], 48.2±10.9 yrs, 59.3% males, 2:1 randomization for training and testing) using the 5hmC‐Seal technique and next‐generation sequencing, a 5hmC‐based clock was constructed to characterize epigenetic ages (5hmC‐age). Epigenetic‐chronological age correlation, median error, and mean aging acceleration were evaluated. An independent set of cfDNA samples collected from 20 subjects (86.2±4.3 yrs, 60.0% males) with pathologically confirmed AD and 17 matched controls on chronological age, sex, and education (86.8±3.8 yrs, 58.8% males) without AD (non‐AD), from the Rush Memory and Aging Project, were employed to calibrate and examine epigenetic aging in AD.ResultChronological ages were found to be associated with the 5hmC modification levels of a significant proportion of genes in HEA, particularly those genes involved in immune response, inflammation, metabolism, and environmental exposure. An epigenetic clock comprised of ∼300 genes was then constructed. In HEA samples, we observed Pearson correlations of 0.88 and 0.65, median errors of 3.7 and 4.9 years, and mean aging accelerations of 0.03 and 0.57 years between chronological age and 5hmC‐age in training and testing samples, respectively, indicating that 5hmC‐age was a robust estimation of chronological age. In the independent small sample of AD and non‐AD subjects, a general acceleration of 5hmC‐ages relative to chronological ages was observed, with a calibrated mean aging acceleration of 2.55 years in persons with AD relative to non‐AD subjects.ConclusionThe 5hmC‐Seal appears to provide a convenient tool to evaluate epigenetic aging in blood that may facilitate preventive and precision medicine. Specifically, accelerated epigenetic aging was found in AD, suggesting that epigenetic age assessed in blood may be a novel biomarker for this neurodegenerative disease. This study was supported partially by the NIH (RF1AG074549, R01AG17917).