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

Weissenburg, A. M., Junge, M. P., Homann, J., Dobricic, V., Vetter, V. M., Lindenberger, U., Lill, C. M., Demuth, I., Duezel, S., Bertram, L.

Luebeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Luebeck, Ratzeburger Allee 160, Building V50, 23562 Luebeck, Germany · medrxiv

Paper

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.

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Research summary

DunedinPACE is identified as a biomarker that consistently associates with cognitive decline in elderly individuals. This paper is relevant as it explores biological age acceleration and its implications for cognitive aging, addressing potential root causes of age-related cognitive decline rather than merely treating symptoms.

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