Biological age acceleration measured by DunedinPACE associates most consistently with cognitive decline in elderly individuals

1 Abstract Background Epigenetic clocks based on DNA methylation (DNAm) have emerged as promising biomarkers of biological aging, yet their associations with cognitive performance remain inconsistent. This study investigates the relationship between epigenetic age acceleration and cognitive performance in older adults using 14 DNAm clocks from five generations of development. Methods We analyzed data from the Berlin Aging Study II (BASE-II) using genome-wide DNAm profiles and cognitive assessments ascertained at baseline (T0) and two follow-up time points (T1, T2) in up to 1,014 individuals. DNAm-based age and age acceleration estimates were calculated using Biolearn and MethylCIPHER. Analyses focused on cross-sectional and longitudinal associations between DNAm clock estimates and cognitive performance, including sex-specific effects and comparisons with frailty as non-cognitive positive control. Results Among all tested DNAm clocks, DunedinPACE (a third-generation clock) showed the strongest and most consistent associations with cognitive performance. In addition, the fifth-generation SystemsAge framework also demonstrated robust associations with cross-sectional and longitudinal cognitive outcomes. In contrast, second-generation clocks (GrimAge [v2], PhenoAge) showed occasional nominal associations, while first-generation clocks (Horvath [v1], Hannum) and the causally-informed, fourth-generation clocks (e.g. YingCausAge, YingDamAge) showed no noteworthy signals. Likewise, telomere length estimated from DNAm was not strongly associated with cognitive performance in this dataset. Conclusions Our findings highlight DunedinPACE as a particularly informative biomarker for various aspects of cognitive aging, while other DNAm aging measures showed no consistent associations. Future work should further refine domain-specific epigenetic biomarkers to improve biological aging assessments and achieve a more reliable early detection of cognitive decline.