Molecular Neurobiology

, Volume 56, Issue 4, pp 2440–2449 | Cite as

The Role of Methylated Circulating Nucleic Acids as a Potential Biomarker in Alzheimer’s Disease

  • Ming-Chyi Pai
  • Yu-Min Kuo
  • I-Fang Wang
  • Po-Min Chiang
  • Kuen-Jer TsaiEmail author


Previous studies report detection of high concentrations of circulating nucleic acids (CNAs), which are likely related to cell apoptosis, in the plasma of patients with cancers, stroke, trauma, and relapsing-remitting multiple sclerosis. However, the relationship between Alzheimer’s disease (AD) and CNAs is unclear. A total of 36 adult participants (9 non-demented controls and 27 patients with AD) and patients with mild AD, who met the criteria for probable AD, were enrolled in the present study, which was conducted at the Department of Neurology of National Cheng Kung University Hospital. The CNA levels were increased in the plasma of patients with AD, culture medium of amyloid-β-treated SH-SY5Y cells, and plasma from a mouse model of AD. The CNA concentrations in the plasma were positively correlated with the cognitive scores. Further, CNAs in patients with AD contained neuronal tissue-specific methylated LHX2, at CpG sites 1 and 5. These results showed that the increased levels of plasma CNAs could be related to neuronal cell death that was induced by β-amyloid toxicity. Thus, the results suggested that the levels of plasma CNAs and LHX2 methylation might serve as potential biomarkers for the diagnosis of AD, particularly during the early stages of the disease.


Alzheimer’s disease Apoptosis Circulating nucleic acids Methylation 



The authors thank M.-T. Yu, C.-H. Pan, and Y.-T. Sun for their technical assistance in the study.

Abbreviations and Acronyms

CNAs, circulating nucleic acids; AD Alzheimer’s disease; LHX2, LIM homeobox 2 gene aCSF, artificial cerebrospinal fluid; CDR, Clinical Dementia Rating; MMSE, Mini-Mental State Examination; CASI, Cognitive Abilities Screening Instrument; MS, multiple sclerosis

Author Contributions

K.-J. Tsai, Y.-M. Kuo, and M.-C. Pai contributed substantially to the conception and design of the research project and its scientific interpretation; K.-J. Tsai wrote the manuscript; I.-F. Wang and P.-M. Chiang took responsibility for the statistical analysis and reporting of the results.

Funding Information

This study was supported by grants from the NCKU Hospital Medical Center (NCKUH-10006002); Ministry of Health, Taiwan (DOH101-TD-B-111-0002); and Ministry of Science and Technology, Taiwan (MOST-104-2745-B-006-001, MOST-105-2628-B-006-016-MY3, and MOST-106-2628-B-006-001-MY4).

Compliance with Ethical Standards

Conflict of Interests

The authors declare that they have no competing interests.

Supplementary material

12035_2018_1229_MOESM1_ESM.pdf (325 kb)
ESM1 (PDF 324 kb)


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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Behavioural Neurology, Department of Neurology, National Cheng Kung University Hospital, College of MedicineNational Cheng Kung UniversityTainanTaiwan
  2. 2.Alzheimer’s Disease Research Centre, National Cheng Kung University Hospital, College of MedicineNational Cheng Kung UniversityTainanTaiwan
  3. 3.Department of Cell Biology and Anatomy, College of MedicineNational Cheng Kung UniversityTainanTaiwan
  4. 4.Institute of Clinical Medicine, College of MedicineNational Cheng Kung UniversityTainanTaiwan
  5. 5.Institute of Molecular BiologyAcademia SinicaTaipeiTaiwan
  6. 6.Research Center of Clinical Medicine, National Cheng Kung University Hospital, College of MedicineNational Cheng Kung UniversityTainanTaiwan

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