Research Paper Volume 12, Issue 20 pp 20817—20834

Hippocampal and cortical tissue-specific epigenetic clocks indicate an increased epigenetic age in a mouse model for Alzheimer’s disease

Emma Coninx1,2, , Yap Ching Chew3, , Xiaojing Yang3, , Wei Guo3, , Amelie Coolkens1, , Sarah Baatout1, , Lieve Moons2, , Mieke Verslegers1, , Roel Quintens1, ,

  • 1 Radiobiology Unit, Institute for Environment, Health and Safety, Belgian Nuclear Research Centre (SCK CEN), Mol 2400, Belgium
  • 2 Neural Circuit Development and Regeneration Research Group, Department of Biology, Katholieke Universiteit Leuven, Leuven 3000, Belgium
  • 3 Epigenetics Technologies, Zymo Research Corporation, Irvine, CA 92614, USA

Received: April 30, 2020       Accepted: August 27, 2020       Published: October 20, 2020
How to Cite

Copyright: © 2020 Coninx et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Epigenetic clocks are based on age-associated changes in DNA methylation of CpG-sites, which can accurately measure chronological age in different species. Recently, several studies have indicated that the difference between chronological and epigenetic age, defined as the age acceleration, could reflect biological age indicating functional decline and age-associated diseases. In humans, an epigenetic clock associated Alzheimer’s disease (AD) pathology with an acceleration of the epigenetic age. In this study, we developed and validated two mouse brain region-specific epigenetic clocks from the C57BL/6J hippocampus and cerebral cortex. Both clocks, which could successfully estimate chronological age, were further validated in a widely used mouse model for AD, the triple transgenic AD (3xTg-AD) mouse. We observed an epigenetic age acceleration indicating an increased biological age for the 3xTg-AD mice compared to non-pathological C57BL/6J mice, which was more pronounced in the cortex as compared to the hippocampus. Genomic region enrichment analysis revealed that age-dependent CpGs were enriched in genes related to developmental, aging-related, neuronal and neurodegenerative functions. Due to the limited access of human brain tissues, these epigenetic clocks specific for mouse cortex and hippocampus might be important in further unravelling the role of epigenetic mechanisms underlying AD pathology or brain aging in general.


3xTg-AD: Triple transgenic Alzheimer’s disease; AD: Alzheimer’s disease; DMR: Differentially methylated regions; GREAT: Genomic enrichment of annotation tool; PCA: Principal component analysis; B6: C57BL/6J; RRBS: reduced representation bisulfite sequencing.