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

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 APOEɛ4 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.

[1]  Ying Han,et al.  Blood NCAPH2 Methylation Is Associated With Hippocampal Volume in Subjective Cognitive Decline With Apolipoprotein E ε4 Non-carriers , 2021, Frontiers in Aging Neuroscience.

[2]  Michael Wagner,et al.  The characterisation of subjective cognitive decline , 2020, The Lancet Neurology.

[3]  Ying Han,et al.  Sino Longitudinal Study on Cognitive Decline (SILCODE): protocol for a Chinese longitudinal observational study to develop risk prediction models of conversion to mild cognitive impairment in individuals with subjective cognitive decline , 2019, BMJ Open.

[4]  P. Malhotra,et al.  Quantitative evaluation of beta-amyloid brain PET imaging in dementia: a comparison between two commercial software packages and the clinical report. , 2019, The British journal of radiology.

[5]  Huy Q. Nguyen,et al.  Condensin II subunit NCAPH2 associates with shelterin protein TRF1 and is required for telomere stability , 2019, Journal of cellular physiology.

[6]  C. Jack,et al.  NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease , 2018, Alzheimer's & Dementia.

[7]  J. Hardy,et al.  Alzheimer's disease , 2018, European journal of neurology.

[8]  D. Mari,et al.  Transcriptional and epigenetic phenomena in peripheral blood cells of monozygotic twins discordant for alzheimer’s disease, a case report , 2017, Journal of the Neurological Sciences.

[9]  Shunjiang Xu,et al.  Elevation of Peripheral BDNF Promoter Methylation Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer's Disease: A 5-Year Longitudinal Study. , 2017, Journal of Alzheimer's disease : JAD.

[10]  Shunichiro Shinagawa,et al.  DNA methylation in the NCAPH2/LMF2 promoter region is associated with hippocampal atrophy in Alzheimer’s disease and amnesic mild cognitive impairment patients , 2016, Neuroscience Letters.

[11]  J. Jeong,et al.  Amyloid Beta-Mediated Hypomethylation of Heme Oxygenase 1 Correlates with Cognitive Impairment in Alzheimer’s Disease , 2016, PloS one.

[12]  Yong He,et al.  Subjective Cognitive Decline: Mapping Functional and Structural Brain Changes-A Combined Resting-State Functional and Structural MR Imaging Study. , 2016, Radiology.

[13]  Shunichiro Shinagawa,et al.  Development of Biomarkers Based on DNA Methylation in the NCAPH2/LMF2 Promoter Region for Diagnosis of Alzheimer’s Disease and Amnesic Mild Cognitive Impairment , 2016, PloS one.

[14]  Kerstin Heurling,et al.  [18F]flutemetamol amyloid positron emission tomography in preclinical and symptomatic Alzheimer's disease: Specific detection of advanced phases of amyloid-β pathology , 2015, Alzheimer's & Dementia.

[15]  Daniel Bandy,et al.  Improved Power for Characterizing Longitudinal Amyloid-β PET Changes and Evaluating Amyloid-Modifying Treatments with a Cerebral White Matter Reference Region , 2015, The Journal of Nuclear Medicine.

[16]  Hisashi Yamada,et al.  Association between DNA Methylation of the BDNF Promoter Region and Clinical Presentation in Alzheimer's Disease , 2015, Dementia and Geriatric Cognitive Disorders Extra.

[17]  K. Nishide,et al.  Overlapping and Non-overlapping Functions of Condensins I and II in Neural Stem Cell Divisions , 2014, PLoS genetics.

[18]  S. Duan,et al.  Elevation of Peripheral BDNF Promoter Methylation Links to the Risk of Alzheimer's Disease , 2014, PloS one.

[19]  Andrew J. Saykin,et al.  A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease , 2014, Alzheimer's & Dementia.

[20]  F. Jessen.  Subjective and objective cognitive decline at the pre-dementia stage of Alzheimer’s disease , 2014, European Archives of Psychiatry and Clinical Neuroscience.

[21]  Ian M. McDonough,et al.  Memory's aging echo: Age-related decline in neural reactivation of perceptual details during recollection , 2014, NeuroImage.

[22]  E. Diamandis,et al.  Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer’s disease patients and controls , 2014, Acta Neuropathologica.

[23]  Guojun Bu,et al.  ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners? , 2014, Neuron.

[24]  R. Lockshin,et al.  Sex‐dependent regulation of cytochrome P450 family members Cyp1a1, Cyp2e1, and Cyp7b1 by methylation of DNA , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[25]  E P Noble,et al.  Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients , 2014, Translational Psychiatry.

[26]  D. Salmon,et al.  Neuropsychological criteria for mild cognitive impairment improves diagnostic precision, biomarker associations, and progression rates. , 2014, Journal of Alzheimer's disease : JAD.

[27]  Margaret R Karagas,et al.  Blood-based profiles of DNA methylation predict the underlying distribution of cell types , 2013, Epigenetics.

[28]  C. Rowe,et al.  Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study , 2013, The Lancet Neurology.

[29]  S. Duan,et al.  Elevated PLA2G7 Gene Promoter Methylation as a Gender-Specific Marker of Aging Increases the Risk of Coronary Heart Disease in Females , 2013, PloS one.

[30]  F. Coppedè,et al.  Comparison Study of MS-HRM and Pyrosequencing Techniques for Quantification of APC and CDKN2A Gene Methylation , 2013, PloS one.

[31]  R. Dobson,et al.  Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood , 2012, Genome Biology.

[32]  A. Baccarelli,et al.  DNA methylation in repetitive elements and Alzheimer disease , 2011, Brain, Behavior, and Immunity.

[33]  Denise C. Park,et al.  Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[34]  M. Albert,et al.  Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[35]  J. Bell,et al.  A Genome-Wide Study of DNA Methylation Patterns and Gene Expression Levels in Multiple Human and Chimpanzee Tissues , 2011, PLoS genetics.

[36]  R. Coleman,et al.  Use of florbetapir-PET for imaging beta-amyloid pathology. , 2011, JAMA.

[37]  J. Rogers,et al.  Epigenetic Differences in Cortical Neurons from a Pair of Monozygotic Twins Discordant for Alzheimer's Disease , 2009, PloS one.

[38]  A. Feinberg,et al.  Intra-individual change over time in DNA methylation with familial clustering. , 2008, JAMA.

[39]  R. Jaenisch,et al.  DNA Methylation in the Human Cerebral Cortex Is Dynamically Regulated throughout the Life Span and Involves Differentiated Neurons , 2007, PloS one.

[40]  Manel Esteller,et al.  Epigenetics and aging: the targets and the marks. , 2007, Trends in genetics : TIG.

[41]  John M. Lee,et al.  Hypomethylation of the amyloid precursor protein gene in the brain of an alzheimer’s disease patient , 2007, Journal of Molecular Neuroscience.

[42]  Patrizia Mecocci,et al.  Mild cognitive impairment: a systematic review. , 2007, Journal of Alzheimer's disease : JAD.

[43]  R. Petersen.  Mild cognitive impairment as a diagnostic entity , 2004, Journal of internal medicine.

[44]  B. Winblad,et al.  Very Old Women at Highest Risk of Dementia and Alzheimer's Disease , 1997, Neurology.