Associations Between Levels of Peripheral NCAPH2 Promoter Methylation and Different Stages of Alzheimer’s Disease: A Cross-Sectional Study

Article type: Research Article

Authors: Hao, Shu-Wen^{a; b; c; 1} | Li, Tao-Ran^{d; e; 1} | Han, Chao^{f; 1} | Han, Ying^{d; f; *} | Cai, Yan-Ning^{a; g; *}

Affiliations: [a] Department of Neurobiology, Xuanwu Hospital, Capital Medical University, Beijing, China | [b] Department of Neurology, The First Hospital of Hebei Medical University, Shijiazhuang, China | [c] Department of Neurology, Hebei Hospital of Xuanwu Hospital Capital Medical University, Shijiazhuang, China | [d] Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China | [e] Department of Neurology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China | [f] National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, China | [g] Department of Biobank, Xuanwu Hospital, Capital Medical University, Beijing, China

Correspondence: [*] Correspondence to: Yan-Ning Cai, PhD, Department of Biobank, Xuanwu Hospital, Capital Medical University, Beijing 100053, China. Tel.: +86 10 83198820; E-mail: [email protected] and Ying Han, MD, Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, China. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Several studies have examined NCAPH2 methylation in amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD), but little is known of NCAPH2 methylation in subjective cognitive decline (SCD). Objective:To examine whether methylation of peripheral NCAPH2 are differentially changed at various phases of AD, and whether it could serve as a diagnostic biomarker for SCD. Methods:A total of 40 AD patients, 52 aMCI patients, 148 SCD patients, and 193 cognitively normal controls (NCs) were recruited in the current case-control study. Besides, 54 cognitively normal individuals have received amyloid positron emission tomography (amyloid PET) scans. Using bisulfite pyrosequencing method, we measured blood DNA methylation in the NCAPH2 gene promoter. Results:The main outcomes were: 1) For SCD, there was no significant difference between SCD and NC regarding NCAPH2 methylation; 2) For aMCI, NCAPH2 methylation at CpG2 were significantly lower in aMCI compared with NC and SCD in the entire population and male subgroup; 3) For AD, NCAPH2 methylation at CpG1 were significantly lower in AD compared with NC among females; 4) A relationship with apolipoprotein E (APOE) ɛ4 status was shown. Receiver operating characteristic (ROC) analysis by combining NCAPH2 methylation, age, education, and APOE ɛ4 status could distinguish between patients with aMCI (area under the curve (AUC): 0.742) and AD (AUC: 0.873) from NCs. Conclusion:NCAPH2 methylation levels were altered at the aMCI and AD stage and may be convenient and cost-effective biomarkers of AD and aMCI.

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, amyloid PET, methylation, NCAPH2, subjective cognitive decline

DOI: 10.3233/JAD-221211

Journal: Journal of Alzheimer's Disease, vol. 92, no. 3, pp. 899-909, 2023