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.
SperlingRA, AisenPS, BeckettLA, BennettDA, CraftS, FaganAM, IwatsuboT, JackCRJr., KayeJ, MontineTJ, ParkDC, ReimanEM, RoweCC, SiemersE, SternY, YaffeK, CarrilloMC, ThiesB, Morrison-BogoradM, WagsterMV, PhelpsCH (2011) 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. Alzheimers Dement7, 280–292.
10.
ThalDR, BeachTG, ZanetteM, HeurlingK, ChakrabartyA, IsmailA, SmithAP, BuckleyC (2015) [(18)F]flutemetamol amyloid positron emission tomography in preclinical and symptomatic Alzheimer’s disease: Specific detection of advanced phases of amyloid-beta pathology. Alzheimers Dement11, 975–985.
VillemagneVL, BurnhamS, BourgeatP, BrownB, EllisKA, SalvadoO, SzoekeC, MacaulaySL, MartinsR, MaruffP, AmesD, RoweCC, MastersCL, Australian Imaging B, Lifestyle Research G (2013) Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: A prospective cohort study. Lancet Neurol12, 357–367.
13.
MastroeniD, McKeeA, GroverA, RogersJ, ColemanPD (2009) Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer’s disease. PLoS One4, e6617.
14.
D’AddarioC, CandiaSB, ArosioB, Di BartolomeoM, AbbateC, CaseA, CandelettiS, RomualdiP, DamantiS, MaccarroneM, BergamaschiniL, MariD (2017) Transcriptional and epigenetic phenomena in peripheral blood cells of monozygotic twins discordant for alzheimer’s disease, a case report. J Neurol Sci372, 211–216.
15.
WestRL, LeeJM, MarounLE (1995) Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer’s disease patient. J Mol Neurosci6, 141–146.
16.
BollatiV, GalimbertiD, PergoliL, Dalla ValleE, BarrettaF, CortiniF, ScarpiniE, BertazziPA, BaccarelliA (2011) DNA methylation in repetitive elements and Alzheimer disease. Brain Behav Immun25, 1078–1083.
17.
XieB, XuY, LiuZ, LiuW, JiangL, ZhangR, CuiD, ZhangQ, XuS (2017) Elevation of Peripheral BDNF Promoter Methylation Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer’s Disease: A 5-Year Longitudinal Study. J Alzheimers Dis56, 391–401.
18.
ChangL, WangY, JiH, DaiD, XuX, JiangD, HongQ, YeH, ZhangX, ZhouX, LiuY, LiJ, ChenZ, LiY, ZhouD, ZhuoR, ZhangY, YinH, MaoC, DuanS, WangQ (2014) Elevation of peripheral BDNF promoter methylation links to the risk of Alzheimer’s disease. PLoS One9, e110773.
19.
NagataT, KobayashiN, IshiiJ, ShinagawaS, NakayamaR, ShibataN, KuerbanB, OhnumaT, KondoK, AraiH, YamadaH, NakayamaK (2015) Association between DNA Methylation of the BDNF Promoter Region and Clinical Presentation in Alzheimer’s Disease. Dement Geriatr Cogn Dis Extra5, 64–73.
20.
KobayashiN, ShinagawaS, NagataT, ShimadaK, ShibataN, OhnumaT, KasanukiK, AraiH, YamadaH, NakayamaK, KondoK (2016) Developmentof biomarkers based on DNA methylation in the NCAPH2/LMF2 promoter region for diagnosis of Alzheimer’s disease and amnesic mild cognitive impairment. PLoS One11, e0146449.
21.
ShinagawaS, KobayashiN, NagataT, KusakaA, YamadaH, KondoK, NakayamaK (2016) DNA methylation in the/LMF2 promoterregion is associated with hippocampal atrophy in Alzheimer’s diseaseand amnesic mild cognitive impairment patients. Neurosci Lett629, 33–37.
22.
LiX, WangX, SuL, HuX, HanY (2019) 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. BMJ Open9, e028188.
23.
CurryS, PatelN, Fakhry-DarianD, KhanS, PerryRJ, MalhotraPA, NijranKS, WinZ (2019) Quantitative evaluation of beta-amyloid brain PET imaging in dementia: A comparison between two commercial software packages and the clinical report. Br J Radiol92, 20181025.
24.
ChenK, RoontivaA, ThiyyaguraP, LeeW, LiuX, AyutyanontN, ProtasH, LuoJL, BauerR, ReschkeC, BandyD, KoeppeRA, FleisherAS, CaselliRJ, LandauS, JagustWJ, WeinerMW, ReimanEM, Alzheimer’s Disease Neuroimaging I (2015) Improved power for characterizing longitudinal amyloid-beta PET changes and evaluating amyloid-modifying treatments with a cerebral white matter reference region. J Nucl Med56, 560–566.
25.
JackCRJr., AlbertMS, KnopmanDS, McKhannGM, SperlingRA, CarrilloMC, ThiesB, PhelpsCH (2011) Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 257–262.
JessenF, AmariglioRE, van BoxtelM, BretelerM, CeccaldiM, ChetelatG, DuboisB, DufouilC, EllisKA, van der FlierWM, GlodzikL, van HartenAC, de LeonMJ, McHughP, MielkeMM, MolinuevoJL, MosconiL, OsorioRS, PerrotinA, PetersenRC, RabinLA, RamiL, ReisbergB, RentzDM, SachdevPS, de la SayetteV, SaykinAJ, ScheltensP, ShulmanMB, SlavinMJ, SperlingRA, StewartR, UspenskayaO, VellasB, VisserPJ, WagnerM, Subjective Cognitive Decline Initiative Working Group (2014) A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer’s disease. Alzheimers Dement10, 844–852.
28.
SunY, DaiZ, LiY, ShengC, LiH, WangX, ChenX, HeY, HanY (2016) Subjective cognitive decline: Mapping functional and structural brain changes-a combined resting-state functional and structural MR imaging study. Radiology281, 185–192.
29.
ChenY, LiTR, HaoSW, WangXN, CaiYN, HanY (2021) Blood NCAPH2 methylation is associated with hippocampal volume in subjective cognitive decline with Apolipoprotein E epsilon4 non-carriers. Front Aging Neurosci13, 632382.
30.
SungHY, ChoiBO, JeongJH, KongKA, HwangJ, AhnJH (2016) Amyloid beta-mediated hypomethylation of heme oxygenase 1 correlates with cognitive impairment in Alzheimer’s disease. PLoS One11, e0153156.
31.
FragaMF, EstellerM (2007) Epigenetics and aging: The targets and the marks. Trends Genet23, 413–418.
32.
SiegmundKD, ConnorCM, CampanM, LongTI, WeisenbergerDJ, BiniszkiewiczD, JaenischR, LairdPW, AkbarianS (2007) DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons. PLoS One2, e895.
33.
BjornssonHT, SigurdssonMI, FallinMD, IrizarryRA, AspelundT, CuiH, YuW, RongioneMA, EkstromTJ, HarrisTB, LaunerLJ, EiriksdottirG, LeppertMF, SapienzaC, GudnasonV, FeinbergAP (2008) Intra-individual change over time in DNA methylation with familial clustering. JAMA299, 2877–2883.
34.
Martinez-MorilloE, HanssonO, AtagiY, BuG, MinthonL, DiamandisEP, NielsenHM (2014) Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer’s disease patients and controls. Acta Neuropathol127, 633–643.
35.
KanekiyoT, XuH, BuG (2014) APOE and Abeta in Alzheimer’sdisease: Accidental encounters or partners?Neuron81, 740–754.
36.
FratiglioniL, ViitanenM, von StraussE, TontodonatiV, HerlitzA, WinbladB (1997) Very old women at highest risk of dementia and Alzheimer’s disease: Incidence data from the Kungsholmen Project, Stockholm. Neurology48, 132–138.
37.
PenalozaCG, EstevezB, HanDM, NorouziM, LockshinRA, ZakeriZ (2014) Sex-dependent regulation of cytochrome P450 family members Cyp1a1, Cyp2e1, and Cyp7b1 by methylation of DNA. FASEB J28, 966–977.
38.
JiangD, ZhengD, WangL, HuangY, LiuH, XuL, LiaoQ, LiuP, ShiX, WangZ, SunL, ZhouQ, LiN, XuL, LeY, YeM, ShaoG, DuanS (2013) Elevated PLA2G7 gene promoter methylation as a gender-specific marker of aging increases the risk of coronary heart disease in females. PLoS One8, e59752.
39.
WallaceHA, RanaV, NguyenHQ, BoscoG (2019) Condensin II subunitassociates with shelterin protein TRF1 and is requiredfor telomere stability. J Cell Physiol234, 20755–20768.
40.
NishideK, HiranoT (2014) Overlapping and non-overlapping functions of condensins I and II in neural stem cell divisions. PLoS Genet10, e1004847.
41.
PaiAA, BellJT, MarioniJC, PritchardJK, GiladY (2011) A genome-wide study of DNA methylation patterns and gene expression levels in multiple human and chimpanzee tissues. PLoS Genet7, e1001316.
42.
MigheliF, StoccoroA, CoppedeF, Wan OmarWA, FailliA, ConsoliniR, SecciaM, SpisniR, MiccoliP, MathersJC, MiglioreL (2013) Comparison study of MS-HRM and pyrosequencing techniques for quantification of APC and CDKN2A gene methylation. PLoS One8, e52501.
43.
WocknerLF, NobleEP, LawfordBR, YoungRM, MorrisCP, WhitehallVL, VoiseyJ (2014) Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients. Transl Psychiatry4, e339.
44.
DaviesMN, VoltaM, PidsleyR, LunnonK, DixitA, LovestoneS, CoarfaC, HarrisRA, MilosavljevicA, TroakesC, Al-SarrajS, DobsonR, SchalkwykLC, MillJ (2012) Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood. Genome Biol13, R43.
45.
KoestlerDC, ChristensenB, KaragasMR, MarsitCJ, LangevinSM, KelseyKT, WienckeJK, HousemanEA (2013) Blood-based profiles of DNA methylation predict the underlying distribution of cell types: A validation analysis. Epigenetics8, 816–826.
