Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

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

The identifiability problem for generalised competing risk models with non-symmetric virtual ages

The identifiability problem is well-known in competing risks (1). Recently a generalised competing risks framework was proposed by Doyen and Gaudoin(2), along with several subclasses of this framework which incorporate virtual age models(3). The identifiability problem is still present in generalised competing risk models with symmetrical virtual ages for each of the risks, however it is unclear to what extent this is true for generalised competing risk models with non-symmetrical virtual ages for the risks. Bedford and Lindqvist(4) have constructed an example of a two component system in which, every time a component fails it is restored to a state "as good as new", while the remaining components are restored to a state "as bad as old". In this example they prove that the model can be uniquely identified. Doyen and Gaudoin(2) show that this example is a particular instance of a generalised competing risks model with non-symmetrical virtual ages. In this paper we generalise the Bedford and Lindqvist example to show identifiability of systems with n components. We also discuss how this proof has been constructed to more easily allow for the consideration of other virtual age models in future work