Second-generation epigenetic clocks and hippocampal volume in AIBL and ADNI
In the AIBL cohort, faster biological ageing estimated by the PCPhenoAge epigenetic clock was associated with hippocampal volume, and this was replicated in ADNI. Other cross-sectional clock associations were not validated in ADNI. [1]
Automatic summary · not editorially reviewed
The key findings
The study examined ten second-generation epigenetic clocks alongside brain volumetrics, brain amyloid-beta burden and cognition in the AIBL and ADNI cohorts. [1]
Age acceleration estimated by the PCPhenoAge clock was significantly associated with hippocampal volume in AIBL, and this was replicated in ADNI. [1]
Other cross-sectional associations, including hippocampal volume with several clocks and a methylation-derived telomere length estimate with change in brain amyloid-beta burden, were not validated in ADNI. [1]
The source at a glance
- Study type / format
- Abstract of an observational cohort study
- Population / context
- Participants in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts
- Summary based on
- Study abstract
- Original publication
- June 20, 2026
Ten second-generation clocks in AIBL and ADNI
The study extended earlier findings on first-generation clocks by examining ten second-generation epigenetic clocks. These clocks use DNA methylation data to predict traits such as age-related health, disease, morbidity and mortality, and the authors describe them as better predictors of health-related traits than most first-generation clocks. The analysis looked at brain volumetrics, brain amyloid-beta burden and cognition in two cohorts: the Australian Imaging, Biomarkers and Lifestyle (AIBL) study and the Alzheimer's Disease Neuroimaging Initiative (ADNI).
Supporting source [1]
PCPhenoAge association replicated in ADNI
Significant associations were found between age acceleration estimated by the Principal Components PhenoAge (PCPhenoAge) clock and hippocampal volume in AIBL, with replication in ADNI. Age acceleration here means the difference between biological and chronological age. Several other significant cross-sectional findings linked hippocampal volume with GrimAge, PCGrimAge, PCHorvathS2013, PCHorvathS2018 and PCHannumG2013, and a DNA methylation-derived estimate of telomere length was associated with change in brain amyloid-beta burden. These other results were not validated in the ADNI cohort.
Supporting source [1]
Cross-sectional associations, not causes
The abstract reports associations only; it does not show that biological ageing causes hippocampal volume differences or Alzheimer's-related changes. The other clock findings are described as cross-sectional, and their failure to replicate in ADNI limits how far they can be generalised. The authors present the work as adding to existing literature on epigenetic clocks, the ageing process and the development of Alzheimer's disease-related traits.
Supporting source [1]
How to interpret this
Abstract only; the full text was not reviewed. The abstract reports associations, not causes, and does not give sample sizes, follow-up or effect sizes. Most findings are cross-sectional and several were not replicated in ADNI.
Based on the study abstract; the full paper, tables and supplementary data were not reviewed.
Source & supporting passages
Milicic L, Vacher M, Doré V, Bourgeat P, Shishegar R, Doecke JD, Maruff P, Rowe CC, Villemagne VL, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Australian Imaging Biomarkers, Lifestyle (AIBL) Study, Porter T, Laws SM. · europepmc.org · June 20, 2026