Circulating Cell-Free Genomic DNA Is Associated with an Increased Risk of Dementia and with Change in Cognitive and Physical Function

J Alzheimers Dis. 2022;89(4):1233-1240. doi: 10.3233/JAD-220301.


Background: Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA).

Objective: The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults.

Methods: We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education.

Results: Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up.

Conclusion: This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty.

Keywords: Cell-free DNA; cell death; cognitive dysfunction; dementia; frailty.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Cell-Free Nucleic Acids*
  • Cognition / physiology
  • Cognitive Dysfunction* / epidemiology
  • Cognitive Dysfunction* / genetics
  • Dementia* / epidemiology
  • Dementia* / genetics
  • Frailty* / psychology
  • Genomics
  • Humans


  • Cell-Free Nucleic Acids