Alzheimer's disease-associated (hydroxy)methylomic changes in the brain and blood

Roy Lardenoije, Janou A. Y. Roubroeks, Ehsan Pishva, Markus Leber, Holger Wagner, Artemis Iatrou, Adam R. Smith, Rebecca G. Smith, Lars M. T. Eijssen, Luca Kleineidam, Amit Kawalia, Per Hoffmann, Tobias Luck, Steffi Riedel-Heller, Frank Jessen, Wolfgang Maier, Michael Wagner, Rene Hurlemann, Gunter Kenis, Muhammad AliAntonio del Sol, Diego Mastroeni, Elaine Delvaux, Paul D. Coleman, Jonathan Mill, Bart P. F. Rutten, Katie Lunnon, Alfredo Ramirez, Daniel L. A. van den Hove*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

42 Citations (Web of Science)

Abstract

Background Late-onset Alzheimer's disease (AD) is a complex multifactorial affliction, the pathogenesis of which is thought to involve gene-environment interactions that might be captured in the epigenome. The present study investigated epigenome-wide patterns of DNA methylation (5-methylcytosine, 5mC) and hydroxymethylation (5-hydroxymethylcytosine, 5hmC), as well as the abundance of unmodified cytosine (UC), in relation to AD. Results We identified epigenetic differences in AD patients (n = 45) as compared to age-matched controls (n = 35) in the middle temporal gyrus, pertaining to genomic regions close to or overlapping with genes such as OXT (- 3.76% 5mC, p(Sidak) = 1.07E-06), CHRNB1 (+ 1.46% 5hmC, p(Sidak) = 4.01E-04), RHBDF2 (- 3.45% UC, p(Sidak) = 4.85E-06), and C3 (- 1.20% UC, p(Sidak) = 1.57E-03). In parallel, in an independent cohort, we compared the blood methylome of converters to AD dementia (n = 54) and non-converters (n = 42), at a preclinical stage. DNA methylation in the same region of the OXT promoter as found in the brain was found to be associated with subsequent conversion to AD dementia in the blood of elderly, non-demented individuals (+ 3.43% 5mC, p(Sidak) = 7.14E-04). Conclusions The implication of genome-wide significant differential methylation of OXT, encoding oxytocin, in two independent cohorts indicates it is a promising target for future studies on early biomarkers and novel therapeutic strategies in AD.

Original languageEnglish
Article number164
Number of pages15
JournalClinical epigenetics
Volume11
Issue number1
DOIs
Publication statusPublished - 27 Nov 2019

Keywords

  • Alzheimer's disease
  • Epigenetics
  • DNA methylation
  • DNA hydroxymethylation
  • Brain
  • Middle temporal gyrus
  • Blood
  • GENOME-WIDE ASSOCIATION
  • DNA METHYLATION
  • GLOBAL CHANGES
  • 5-HYDROXYMETHYLCYTOSINE
  • OXYTOCIN
  • DEMENTIA
  • HYDROXYMETHYLATION
  • HEALTH
  • ROLES
  • COGNITION

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