Research Paper Volume 14, Issue 4 pp 1691—1712

Mid-life epigenetic age, neuroimaging brain age, and cognitive function: coronary artery risk development in young adults (CARDIA) study

Yinan Zheng1, *, , Mohamad Habes2,3, *, , Mitzi Gonzales2, , Raymond Pomponio3, , Ilya Nasrallah3, , Sadiya Khan1,4, , Douglas E. Vaughan5, , Christos Davatzikos3, , Sudha Seshadri2,6, , Lenore Launer7, , Farzaneh Sorond8, , Sanaz Sedaghat9, , Derek Wainwright10, , Andrea Baccarelli11, , Stephen Sidney12, , Nick Bryan13, , Philip Greenland1, , Donald Lloyd-Jones1, , Kristine Yaffe14,15,16,17, #, , Lifang Hou1, #, ,

  • 1 Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
  • 2 Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
  • 3 Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA
  • 4 Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
  • 5 Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
  • 6 Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
  • 7 Laboratory of Epidemiology and Population Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
  • 8 Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
  • 9 Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA
  • 10 Departments of Neurological Surgery, Medicine-Hematology and Oncology, Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
  • 11 Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY 10032, USA
  • 12 Kaiser Permanente Division of Research, Oakland, CA 94612, USA
  • 13 Department of Diagnostic Medicine, Dell Medical School, University of Texas at Austin, Austin, TX 78712, USA
  • 14 Departments of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA 94143, USA
  • 15 Department of Neurology University of California, San Francisco, CA 94143, USA
  • 16 Department of Epidemiology and Biostatistics, University of California San Francisco, CA 94143, USA
  • 17 San Francisco VA Medical Center, San Francisco, CA 94143, USA
* Equal contribution
# Co-senior author

Received: July 7, 2021       Accepted: February 8, 2022       Published: February 27, 2022
How to Cite

Copyright: © 2022 Zheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


The proportion of aging populations affected by dementia is increasing. There is an urgent need to identify biological aging markers in mid-life before symptoms of age-related dementia present for early intervention to delay the cognitive decline and the onset of dementia. In this cohort study involving 1,676 healthy participants (mean age 40) with up to 15 years of follow up, we evaluated the associations between cognitive function and two classes of novel biological aging markers: blood-based epigenetic aging and neuroimaging-based brain aging. Both accelerated epigenetic aging and brain aging were prospectively associated with worse cognitive outcomes. Specifically, every year faster epigenetic or brain aging was on average associated with 0.19-0.28 higher (worse) Stroop score, 0.04-0.05 lower (worse) RAVLT score, and 0.23-0.45 lower (worse) DSST (all false-discovery-rate-adjusted p <0.05). While epigenetic aging is a more stable biomarker with strong long-term predictive performance for cognitive function, brain aging biomarker may change more dynamically in temporal association with cognitive decline. The combined model using epigenetic and brain aging markers achieved the highest accuracy (AUC: 0.68, p<0.001) in predicting global cognitive function status. Accelerated epigenetic age and brain age at midlife may aid timely identification of individuals at risk for accelerated cognitive decline and promote the development of interventions to preserve optimal functioning across the lifespan.


CARDIA: Coronary Artery Risk Development in Young Adults study; RAVLT: Rey Auditory Verbal Learning Test; DSST: Digital Symbol Substitution Test; GrimAA: GrimAge Acceleration; PhenoAA: PhenoAge Acceleration; EEAA: Extrinsic Epigenetic Age Acceleration; IEAA: Intrinsic Epigenetic Age Acceleration; MRI: Magnetic Resonance Imaging; SPARE: Spatial Patterns of Abnormality for Recognition; BAA: Brain Age Acceleration; FDR: False Discovery Rate; OR: Odds Ratio; ROC: Receiver Operating Characteristic; CI: Confidence Intervals; AUC: Area Under the ROC Curve.