Abstract
In order to conduct early therapeutic interventions for Alzheimer’s disease (AD), convenient, early diagnosis markers are required. We previously reported that changes in DNA methylation levels were associated with amnestic mild cognitive impairment (aMCI) and AD. As the results suggested changes in DNA methylation levels in the COASY and SPINT1 gene promoter regions, in the present study we examined DNA methylation in these regions in normal controls (NCs, n = 30), aMCI subjects (n = 28) and AD subjects (n = 30) using methylation-sensitive high resolution melting (MS-HRM) analysis. The results indicated that DNA methylation in the two regions was significantly increased in AD and aMCI as compared to NCs (P < 0.0001, P < 0.0001, ANOVA). Further analysis suggested that DNA methylation in the COASY gene promoter region in particular could be a high sensitivity, high specificity diagnosis biomarker (COASY: sensitivity 96.6%, specificity 96.7%; SPINT1: sensitivity 63.8%, specificity 83.3%). DNA methylation in the COASY promoter region was associated with CDR Scale Sum of Boxes (CDR-SB), an indicator of dementia severity. In the SPINT1 promoter region, DNA methylation was negatively associated with age in NCs and elevated in aMCI and AD subjects positive for antibodies to Herpes simplex virus type 1 (HSV-1). These findings suggested that changes in DNA methylation in the COASY and SPINT1 promoter regions are influenced by various factors. In conclusion, DNA methylation levels in the COASY and SPINT1 promoter regions were considered to potentially be a convenient and useful biomarker for diagnosis of AD and aMCI.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by cognitive dysfunction, of which memory impairment is a typical feature, and the disease goes through the prior stage of amnestic mild cognitive impairment before onset [1]
mini-mental state examination (MMSE), CDR Scale Sum of Boxes (CDR-SB) and BEHAVE-AD scores were significantly different between the AD group and the amnestic mild cognitive impairment (aMCI) group, and there was a high prevalence of APOE allele 4 in the AD group
We measured DNA methylation by methylation-sensitive high resolution melting (MS-HRM) in the promoter regions of the COASY and SPINT1 genes, which the results of previous screening had indicated as candidate genes
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by cognitive dysfunction, of which memory impairment is a typical feature, and the disease goes through the prior stage of amnestic mild cognitive impairment (aMCI) before onset [1]. The pathophysiological process of AD is thought to begin many years before diagnosis [2], and though therapeutic interventions are desirable at this stage, diagnosis is difficult. We need to develop biomarkers that can predict progression to aMCI and AD. Some of the known procedures for the early diagnosis of AD are amyloid imaging using positron-emission tomography (PET) [3], and measurement of amyloidβ (Aβ) or tau in cerebrospinal fluid (CSF) [4, 5]. Lacking specificity and convenience, and being invasive, they have shortcomings as diagnosis tools. There is a great need to develop convenient new blood biomarkers
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