Milicic, LidijaVacher, MichaelPorter, TenielleDoré, VincentBurnham, Samantha C.Bourgeat, PierrickShishegar, RositaDoecke, JamesArmstrong, Nicola J.Tankard, RickMaruff, PaulMasters, Colin L.Rowe, Christopher C.Villemagne, Victor L.Laws, Simon M.Alzheimer’s Disease Neuroimaging Initiative (ADNI)Australian Imaging Biomarkers and Lifestyle (AIBL) Study2024-10-252024-10-252022Milicic L, Vacher M, Porter T, et al. Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume. Geroscience. 2022;44(3):1807-1823. doi:10.1007/s11357-022-00558-8https://hdl.handle.net/1805/44223The 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.en-USAttribution 4.0 InternationalDNA methylationEpigeneticsAlzheimer’s diseaseHippocampal volumeCognitionAgeingArticle