Analysis of second-generation epigenetic clocks reveals further associations between disproportionate biological ageing and hippocampal volume

Age acceleration, or the difference between biological and chronological age, is a research area of growing interest, particularly in the field of age-related and neurodegenerative disorders, including Alzheimer's disease (AD). First-generation epigenetic clocks that predict chronological age utilising DNA methylation data were the first to derive estimates of age acceleration, which have been associated with several age-related conditions. More recently, second-generation epigenetic clocks that are predictors of specific traits such as age-related health, disease or morbidity and mortality phenotypes have been developed. These are considered better predictors of health-related traits and show stronger associations with lifespan and mortality than most first-generation clocks. This study aimed to extend on our previous findings of associations of first-generation clocks with hippocampal volume, by investigating the relationship between ten second-generation clocks and brain volumetrics, brain Aβ burden and cognition in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts. Significant associations were found between age acceleration, as estimated by the Principal Components PhenoAge (PCPhenoAge) epigenetic clock(definition), and hippocampal volume in the AIBL study, with replication in the ADNI dataset. Several other significant cross-sectional findings were observed between hippocampal volume and GrimAge, PCGrimAge, PCHorvathS2013, PCHorvathS2018 and PCHannumG2013 and between a DNA methylation-derived estimate of telomere(definition) length and change in brain Aβ burden. However, these results were not validated in the ADNI cohort. This investigation of second-generation epigenetic clocks further adds to the body of existing literature on the application of epigenetic clocks in relation to the ageing process and in the development of AD-related traits.