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Peer-reviewedCC BYFrontiers in aging neuroscience

Serum neuron-derived extracellular vesicle mitochondrial DNA as a potential biomarker for mild cognitive impairment due to AD

  • Danhong Lin1
  • Yashi Luo1
  • Xiaxia Qiu1
  • Peng Ye2
  • Rongbing Chen1
  • Wenshen Xu1
  • Ru Zheng1
  • Xiaomeng Fu1
  • Kengna Fan1
  • Dengbin Chen1
  • Bin Yang1
  • Longfei Chen3
2 more authors
  • Qishui Ou1
  • Xiaofeng Liu2
  1. 1Department of Laboratory Medicine, The First Affiliated Hospital, Fujian Medical University , ,
  2. 2Department of Laboratory Medicine, Geriatric Hospital Affiliated to Wuhan University of Science and Technology , ,
  3. 3Department of Neurology, The First Affiliated Hospital, Fujian Medical University , ,
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Abstract

Background

Mild cognitive impairment (MCI) represents the initial clinical manifestation, eventually evolving into the distinctive features of Alzheimer's disease (AD), making its early identification crucial. Notably, mitochondrial dysfunction is an early characteristic of AD. Neuron-derived extracellular vesicles (NDEVs) can cross the blood-brain barrier, and their mitochondrial DNA (mtDNA) can reflect intracerebral lesions, showing considerable potential. In this study, we investigated the alterations in mtDNA within serum NDEVs and evaluated their potential as early diagnostic biomarkers for MCI due to AD.Methods

A total of 42 MCI patients, 49 AD patients, and 57 age-matched cognitively unimpaired (CU) controls were enrolled. Serum NDEVs were enriched and characterized, and their mtDNA levels were quantified by qPCR. ROC curve was used to analyze diagnostic performance, and the integration of multimodal biomarkers was explored.Results

Serum NDEVs mtDNA levels were decreased in patients with AD-MCI, and a significant positive correlation was observed between serum NDEVs mtDNA levels and MMSE scores in MCI patients (r = 0.4864, P = 0.0407), and a similar association was observed in the AD group (r = 0.3857, P = 0.0469). In terms of diagnostic performance, serum NDEV mtDNA demonstrated outstanding discrimination between CU controls and AD subjects, achieving an area under the curve (AUC) of 0.965 (95% CI: 0.933-0.997), with 97.92% sensitivity and 89.09% specificity. Moreover, it also demonstrated moderate efficacy in differentiating early MCI from AD (AUC = 0.736, 95% CI: 0.629-0.842; sensitivity = 72.92%, specificity = 66.67%). In exploratory analyses of clinical and metabolic factors, serum NDEV mtDNA levels were positively correlated with HCY in MCI patients, while in AD patients, NDEV mtDNA levels were elevated in those with diabetes and positively correlated with TG. Notably, integrating NDEV mtDNA with established biomarkers, including p-Tau 217, GFAP, and APOE ε4 carrier status, significantly improved the accuracy of MCI detection, highlighting its value in multimodal biomarker strategies.Conclusion

Serum NDEVs mtDNA levels were significantly reduced in patients with MCI and AD, suggesting strong potential as an early diagnostic biomarker for MCI due to AD.

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Cite

BibTeXRIS
BibTeX
@article{lin2026serum,
  title = {{Serum neuron-derived extracellular vesicle mitochondrial DNA as a potential biomarker for mild cognitive impairment due to AD}},
  author = {Danhong Lin and Yashi Luo and Xiaxia Qiu and Peng Ye and Rongbing Chen and Wenshen Xu and Ru Zheng and Xiaomeng Fu and Kengna Fan and Dengbin Chen and Bin Yang and Longfei Chen and Qishui Ou and Xiaofeng Liu},
  journal = {Frontiers in aging neuroscience},
  year = {2026},
  month = oct,
  doi = {10.3389/fnagi.2026.1924123},
  url = {https://europepmc.org/article/PMC/PMC13716654},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Serum neuron-derived extracellular vesicle mitochondrial DNA as a potential biomarker for mild cognitive impairment due to AD
AU  - Danhong Lin
AU  - Yashi Luo
AU  - Xiaxia Qiu
AU  - Peng Ye
AU  - Rongbing Chen
AU  - Wenshen Xu
AU  - Ru Zheng
AU  - Xiaomeng Fu
AU  - Kengna Fan
AU  - Dengbin Chen
AU  - Bin Yang
AU  - Longfei Chen
AU  - Qishui Ou
AU  - Xiaofeng Liu
PY  - 2026
DA  - 2026/10/15
JO  - Frontiers in aging neuroscience
DO  - 10.3389/fnagi.2026.1924123
UR  - https://europepmc.org/article/PMC/PMC13716654
AB  - Background  Mild cognitive impairment (MCI) represents the initial clinical manifestation, eventually evolving into the distinctive features of Alzheimer's disease (AD), making its early identification crucial. Notably, mitochondrial dysfunction is an early characteristic of AD. Neuron-derived extracellular vesicles (NDEVs) can cross the blood-brain barrier, and their mitochondrial DNA (mtDNA) can reflect intracerebral lesions, showing considerable potential. In this study, we investigated the alterations in mtDNA within serum NDEVs and evaluated their potential as early diagnostic biomarkers for MCI due to AD.Methods  A total of 42 MCI patients, 49 AD patients, and 57 age-matched cognitively unimpaired (CU) controls were enrolled. Serum NDEVs were enriched and characterized, and their mtDNA levels were quantified by qPCR. ROC curve was used to analyze diagnostic performance, and the integration of multimodal biomarkers was explored.Results  Serum NDEVs mtDNA levels were decreased in patients with AD-MCI, and a significant positive correlation was observed between serum NDEVs mtDNA levels and MMSE scores in MCI patients (r = 0.4864, P = 0.0407), and a similar association was observed in the AD group (r = 0.3857, P = 0.0469). In terms of diagnostic performance, serum NDEV mtDNA demonstrated outstanding discrimination between CU controls and AD subjects, achieving an area under the curve (AUC) of 0.965 (95% CI: 0.933-0.997), with 97.92% sensitivity and 89.09% specificity. Moreover, it also demonstrated moderate efficacy in differentiating early MCI from AD (AUC = 0.736, 95% CI: 0.629-0.842; sensitivity = 72.92%, specificity = 66.67%). In exploratory analyses of clinical and metabolic factors, serum NDEV mtDNA levels were positively correlated with HCY in MCI patients, while in AD patients, NDEV mtDNA levels were elevated in those with diabetes and positively correlated with TG. Notably, integrating NDEV mtDNA with established biomarkers, including p-Tau 217, GFAP, and APOE ε4 carrier status, significantly improved the accuracy of MCI detection, highlighting its value in multimodal biomarker strategies.Conclusion  Serum NDEVs mtDNA levels were significantly reduced in patients with MCI and AD, suggesting strong potential as an early diagnostic biomarker for MCI due to AD.
SN  - 1663-4365
ER  -