Elevation of Peripheral BDNF Promoter Methylation Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer’s Disease: A 5-Year Longitudinal Study

Article type: Research Article

Authors: Xie, Bing^{a; 1} | Xu, Yao^{b; 1} | Liu, Zanchao^c | Liu, Wenxuan^d | Jiang, Lei^a | Zhang, Rui^a | Cui, Dongsheng^a | Zhang, Qingfu^e | Xu, Shunjiang^{a; *}

Affiliations: [a] Central Laboratory, The First Hospital of Hebei Medical University, Shijiazhuang, P.R. China | [b] Division of Nephrology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, P.R. China | [c] Department of Endocrinology, The Second Hospital of Shijiazhuang City, Shijiazhuang, P.R. China | [d] Department of Epidemiology and Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, P.R. China | [e] Burn Engineering Center of Hebei Province, Shijiazhuang, P.R. China

Correspondence: [*] Correspondence to: Shunjiang Xu, PhD, Central Laboratory, The First Hospital of Hebei, Medical University, No. 89, Donggang Road, Shijiazhuang 050031, China. Tel.: +86 311 8591 7257; Fax: +86 311 8591 7290; E-mail: sjxu66@hotmail.com.

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

Abstract: Epigenetic aberrations have been identified as biomarkers to predict the risk of Alzheimer’s disease (AD). This study aimed to evaluate whether altered DNA methylation status of BDNF promoter could be used as potential epigenetic biomarkers for predicting the progression from amnestic mild cognitive impairment (aMCI) to AD. A total of 506 aMCI patients and 728 cognitively normal controls were recruited in the cross-sectional analyses. Patients (n = 458) from aMCI cohort were classified into two groups after 5-year follow-up: aMCI-stable group (n = 330) and AD-conversion group (n = 128). DNA methylation of BDNF promoter was detected by bisulfite-PCR amplification and pyrosequencing. The DNA methylation levels of CpG1 and CpG2 in promoter I and CpG5 and CpG6 in promoter IV of BDNF gene were significantly higher in the aMCI group than in the control group at baseline and also were increased in the conversion group compared with the non-conversion group at 5-year follow up time point. CpG5 in BDNF promoter IV had the highest AUC of 0.910 (95% CI: 0.817–0.983, p < 0.05). Kaplan-Meier analysis showed a significant AD conversion propensity for aMCI patients with high methylation levels of CpG5 (HR = 1.96, 95% CI: 1.07–2.98, p < 0.001). Multivariate Cox regression analysis revealed elevated methylation status of CpG5 was a significant independent predictor for AD conversion (HR = 3.51, p = 0.013). These results suggest that elevation of peripheral BDNF promoter methylation might be used as potential epigenetic biomarkers for predicting the conversion from aMCI to AD.

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, BDNF promoter, DNA methylation, follow-up study

DOI: 10.3233/JAD-160954

Journal: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 391-401, 2017