Document Type

Journal Article

Publication Title





School of Medical and Health Sciences / Centre for Precision Health




Edith Cowan University (ECU),

Mental Health Research Institute (MHRI),

National Ageing Research Institute (NARI),

Austin Health, CogState Ltd.

National Health and Medical Research Council (NHMRC)

Dementia Collaborative Research Centres program (DCRC2),

Science and Industry Endowment Fund (SIEF), Cooperative Research Centre (CRC) for Mental Health

Funding for this research was also supported through a NHMRC grant (GNT1161706).

Grant Number

NHMRC Number : GNT1161706


Milicic, L., Vacher, M., Porter, T., Doré, V., Burnham, S. C., Bourgeat, P., ... & Laws, S. M. (2022). Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume. GeroScience, 1-17.


The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes.



Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.