Research Paper Volume 13, Issue 19 pp 22666—22689

Increased plasma brain-derived neurotrophic factor (BDNF) as a potential biomarker for and compensatory mechanism in mild cognitive impairment: a case-control study

Ted Kheng Siang Ng1,2,3,4, , Christina Coughlan5, , Patricia C. Heyn2,6, , Alex Tagawa2,6, , James J. Carollo2,6, , Ee Heok Kua1,7, , Rathi Mahendran1,7, ,

  • 1 Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
  • 2 University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
  • 3 Arizona State University, Edson College of Nursing and Health Innovation, Phoenix, AZ 85004, USA
  • 4 National Cheng Kung University, Institute of Behavioral Medicine, College of Medicine, Tainan 701, Taiwan
  • 5 University of Colorado Alzheimer’s and Cognition Center (CUACC), Department of Neurology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
  • 6 Children’s Hospital Colorado, Center for Gait and Movement Analysis (CGMA), Aurora, CO 80045, USA
  • 7 Department of Psychological Medicine, National University Hospital, Singapore 119228, Singapore

Received: May 5, 2021       Accepted: September 18, 2021       Published: October 15, 2021
How to Cite

Copyright: © 2021 Ng 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.


Background: Previous meta-analyses examining the continuum of Alzheimer’s disease (AD) concluded significantly decreased peripheral brain-derived neurotrophic factor (BDNF) in AD. However, across different meta-analyses, there remain inconsistent findings on peripheral BDNF levels in individuals with mild cognitive impairment (MCI). This issue has been attributed to the highly heterogenous clinical and laboratory factors. Thus, BDNF’s level, discriminative accuracy for identifying all-cause MCI and its subtypes, and its associations with other biomarkers and neurocognitive domains, remain largely unknown.

Methods: To address this heterogeneity, we compared a healthy control cohort (n=56, 45 female) to an MCI cohort (n=40, 28 female), to determine whether plasma BDNF, hs-CRP, and DHEA-S can differentiate healthy from MCI individuals, including two MCI subtypes (amnestic [aMCI] and non-amnestic [non-aMCI]). The associations between BDNF with other biomarkers and neurocognitive tests were examined. Adults with cerebral palsy were included as sensitivity analyses.

Results: Compared to healthy controls, BDNF was significantly higher in all-cause MCI, aMCI, and non-aMCI. Furthermore, BDNF had good (AUC=0.84, 95% CI=0.74 to 0.95, p<0.001) and excellent discriminative accuracies (AUC=0.92, 95% CI=0.84 to 1.00, p<0.001) for all-cause MCI and non-amnestic MCI, respectively. BDNF was significantly and positively associated with plasma hs-CRP (β=0.26, 95% CI=0.02 to 0.50, p=0.038), despite attenuated association upon controlling for BMI (β=0.15, 95% CI=-0.08 to 0.38, p=0.186). Multiple inverse associations between BDNF and detailed neurocognitive tests were also detected.

Conclusions: These findings suggest BDNF is increased as a compensatory mechanism in preclinical dementia, supporting the neurotrophic and partially the inflammatory hypotheses of cognitive impairment.


MCI: mild cognitive impairment; AD: Alzheimer’s disease; non-aMCI: non-amnestic-MCI; HPA: hypothalamic–pituitary–adrenal; MDD: have co-morbid major depressive disorder; GAD: generalized anxiety disorder; hs-CRP: C-reactive protein; DHEA-S: dehydroepiandrosterone sulfate; HPA: hypothalamic–pituitary–adrenal axis; CP: cerebral palsy; HC: healthy control; SD: standard deviation; AUC: area under the curve; ROCs: receiver operating characteristic curves; SPSS: Statistical Package for the Social Sciences.