Research on the mitochondrial genome variants of Alzheimer's disease (AD) in Chinese populations is lacking.
Objective
The study aimed to identify mitochondrial DNA (mtDNA) variants associated with AD risk and explore the relationship between mtDNA variants and plasma biomarkers in AD patients.
Methods
Whole genome sequencing was performed in 1509 AD patients and 2010 controls from the Chinese population. mtDNA variants were called according to GATK's best practice mitochondrial pipeline. We evaluated the association of AD risk with mtDNA variants and mitochondrial haplogroup. Common variant (MAF≥0.01) based association analysis and gene-based tests of rare variants (MAF<0.01) were carried out with PLINK 1.9 and SKAT-O, respectively. Spearman correlation analysis was performed to assess the association between the burden of mtDNA variants and plasma biomarker levels.
Results
The frequency of mitochondrial haplogroup G in AD group was nominally higher than control group (p = 0.019, OR = 1.48). Rare variants of MT-CYB gene were significantly enriched in controls compared to AD patients (p = 2.81 × 10−4, OR = 0.886). Besides, the control group exhibited considerably lower mRNA expression of MT-CYB in brain regions compared to AD patients in GEO database. Furthermore, the number of mtDNA indel variants per individual correlated positively with plasma Aβ42 levels.
Conclusions
Mitochondrial haplogroup G may serve as a risk factor for AD, while rare variants of MT-CYB gene acted as protective factor against AD in mainland China. Moreover, mtDNA variants were related to AD plasma biomarker levels. Our findings highlighted the role of mitochondrial genome variants in the pathogenesis of AD.
WingoTSLahJJLeveyAI, et al.Autosomal recessive causes likely in early-onset Alzheimer disease. Arch Neurol2012; 69: 59–64.
2.
ReitzCPericak-VanceMAForoudT, et al.A global view of the genetic basis of Alzheimer disease. Nat Rev Neurol2023; 19: 261–277.
3.
BellenguezCGrenier-BoleyBLambertJC. Genetics of Alzheimer's disease: where we are, and where we are going. Curr Opin Neurobiol2020; 61: 40–48.
4.
SunBBKurkiMIFoleyCN, et al.Genetic associations of protein-coding variants in human disease. Nature2022; 603: 95–102.
5.
XiaoXLiuHYaoR, et al.LMTK2 And CRB1 are two novel risk genes for Alzheimer's disease in Han Chinese. J Prev Alzheimers Dis2025; 12: 100087.
6.
ChenHHPettyLEShaJ, et al.Genetically regulated expression in late-onset Alzheimer's disease implicates risk genes within known and novel loci. Transl Psychiatry2021; 11: 618.
7.
WangWZhaoFMaX, et al.Mitochondria dysfunction in the pathogenesis of Alzheimer's disease: recent advances. Mol Neurodegener2020; 15: 30.
8.
FleckDPhuLVerschuerenE, et al.PTCD1 Is required for mitochondrial oxidative-phosphorylation: possible genetic association with Alzheimer's disease. J Neurosci2019; 39: 4636–4656.
9.
AshleighTSwerdlowRHBealMF. The role of mitochondrial dysfunction in Alzheimer's disease pathogenesis. Alzheimers Dement2023; 19: 333–342.
10.
EdlandSDSilvermanJMPeskindER, et al.Increased risk of dementia in mothers of Alzheimer's disease cases: evidence for maternal inheritance. Neurology1996; 47: 254–256.
11.
Gómez-TortosaEBarqueroMSBarónM, et al.Variability of age at onset in siblings with familial Alzheimer disease. Arch Neurol2007; 64: 1743–1748.
12.
SeshadriSWolfPABeiserA, et al.Lifetime risk of dementia and Alzheimer's disease. The impact of mortality on risk estimates in the Framingham study. Neurology1997; 49: 1498–1504.
13.
HoneaRASwerdlowRHVidoniED, et al.Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease. Neurology2010; 74: 113–120.
14.
HoneaRASwerdlowRHVidoniED, et al.Progressive regional atrophy in normal adults with a maternal history of Alzheimer disease. Neurology2011; 76: 822–829.
15.
MosconiLRinneJOTsuiWH, et al.Increased fibrillar amyloid-{beta} burden in normal individuals with a family history of late-onset Alzheimer's. Proc Natl Acad Sci U S A2010; 107: 5949–5954.
16.
SwerdlowRHBurnsJMKhanSM. The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta2014; 1842: 1219–1231.
17.
Ruiz-PesiniEMishmarDBrandonM, et al.Effects of purifying and adaptive selection on regional variation in human mtDNA. Science2004; 303: 223–226.
18.
ZhangXFarrellJJTongT, et al.Association of mitochondrial variants and haplogroups identified by whole exome sequencing with Alzheimer's disease. Alzheimers Dement2022; 18: 294–306.
19.
LiuHZhangYZhaoH, et al.The heterogeneity among subgroups of haplogroup J influencing Alzheimer's disease risk. J Adv Res2021; 33: 117–126.
20.
BiRZhangWYuD, et al.Mitochondrial DNA haplogroup B5 confers genetic susceptibility to Alzheimer's disease in Han Chinese. Neurobiol Aging2015; 36: 1604.e1607–1616.
21.
NakamuraAKanekoNVillemagneVL, et al.High performance plasma amyloid-β biomarkers for Alzheimer's disease. Nature2018; 554: 249–254.
22.
ZettergrenALordJAshtonNJ, et al.Association between polygenic risk score of Alzheimer's disease and plasma phosphorylated tau in individuals from the Alzheimer's disease neuroimaging initiative. Alzheimers Res Ther2021; 13: 17.
23.
JackCRJrAlbertMSKnopmanDS, et al.Introduction to the recommendations from the national institute on aging-Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement2011; 7: 257–262.
24.
KleinHUTrumpffCYangHS, et al.Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer's disease brain. Mol Neurodegener2021; 16: 75.
25.
LaricchiaKMLakeNJWattsNA, et al.Mitochondrial DNA variation across 56,434 individuals in gnomAD. Genome Res2022; 32: 569–582.
26.
WeiWSchonKRElgarG, et al.Nuclear-embedded mitochondrial DNA sequences in 66,083 human genomes. Nature2022; 611: 105–114.
27.
Soto-CalderónIDClarkNJWildschutteJV, et al.Identification of species-specific nuclear insertions of mitochondrial DNA (numts) in gorillas and their potential as population genetic markers. Mol Phylogenet Evol2014; 81: 61–70.
28.
WangKLiMHakonarsonH. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res2010; 38: e164.
29.
van OvenMKayserM. Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation. Hum Mutat2009; 30: E386–E394.
30.
Yonova-DoingECalabreseCGomez-DuranA, et al.An atlas of mitochondrial DNA genotype-phenotype associations in the UK Biobank. Nat Genet2021; 53: 982–993.
31.
CalabreseCSimoneDDiromaMA, et al.MToolbox: a highly automated pipeline for heteroplasmy annotation and prioritization analysis of human mitochondrial variants in high-throughput sequencing. Bioinformatics2014; 30: 3115–3117.
32.
NiroulaAVihinenM. PON-mt-tRNA: a multifactorial probability-based method for classification of mitochondrial tRNA variations. Nucleic Acids Res2016; 44: 2020–2027.
33.
Ruiz-PesiniELottMTProcaccioV, et al.An enhanced MITOMAP with a global mtDNA mutational phylogeny. Nucleic Acids Res2007; 35: D823–D828.
34.
ClimaRPresteRCalabreseC, et al.HmtDB 2016: data update, a better performing query system and human mitochondrial DNA haplogroup predictor. Nucleic Acids Res2017; 45: D698–d706.
35.
ShenLDiromaMAGonzalezM, et al.MSeqDR: a centralized knowledge repository and bioinformatics web resource to facilitate genomic investigations in mitochondrial disease. Hum Mutat2016; 37: 540–548.
36.
Bayona-BafaluyMPLópez-GallardoEEmperadorS, et al.Is population frequency a useful criterion to assign pathogenicity to newly described mitochondrial DNA variants?Orphanet J Rare Dis2022; 17: 316.
37.
SzirakiALuZLeeJ, et al.A global view of aging and Alzheimer's pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains. Nat Genet2023; 55: 2104–2116.
38.
XuTWengLZhangC, et al.Genetic spectrum features and diagnostic accuracy of four plasma biomarkers in 248 Chinese patients with frontotemporal dementia. Alzheimers Dement2024; 20: 7281–7295.
39.
HudsonGNallsMEvansJR, et al.Two-stage association study and meta-analysis of mitochondrial DNA variants in PARKINSON disease. Neurology2013; 80: 2042–2048.
40.
SwerdlowRHHuiDChaliseP, et al.Exploratory analysis of mtDNA haplogroups in two Alzheimer's longitudinal cohorts. Alzheimers Dement2020; 16: 1164–1172.
41.
TakasakiS. Mitochondrial haplogroups associated with Japanese Alzheimer's patients. J Bioenerg Biomembr2009; 41: 407–410.
42.
TakasakiS. Mitochondrial SNPs associated with Japanese centenarians, Alzheimer's patients, and Parkinson's patients. Comput Biol Chem2008; 32: 332–337.
43.
YangCWLiCILiuCS, et al.Mitochondrial DNA haplogroup D and brain microstructure regulate cognitive function among community-dwelling older adults. Arch Gerontol Geriatr2024; 117: 105197.
44.
ShererTBBetarbetRStoutAK, et al.An in vitro model of Parkinson's disease: linking mitochondrial impairment to altered alpha-synuclein metabolism and oxidative damage. J Neurosci2002; 22: 7006–7015.
45.
TropeanoCVLa MorgiaCAchilliA, et al.Adult leigh syndrome associated with the m.15635T>C mitochondrial DNA variant affecting the cytochrome b (MT-CYB) gene. Int J Mol Sci2025; 26: 1116.
46.
Petrovic PajicSFakinAJarc-VidmarM, et al.Atypical Leber hereditary optic neuropathy (LHON) associated with a novel MT-CYB:m.15309T>C(Ile188Thr) variant. Genes (Basel)2025; 16: 108.
47.
ZarroukSFinstererJMehriS, et al.Dilated cardiomyopathy due to the novel MT-CYB missense mutation m.14757T>C. J Med Cases2021; 12: 455–459.
48.
JancicJRovcaninBDjuricV, et al.Analysis of secondary mtDNA mutations in families with Leber's hereditary optic neuropathy: four novel variants and their association with clinical presentation. Mitochondrion2020; 50: 132–138.
49.
RonchiDCosiATondutiD, et al.Clinical and molecular features of an infant patient affected by Leigh disease associated to m.14459G>A mitochondrial DNA mutation: a case report. BMC Neurol2011; 11: 85.
50.
LandrumMJLeeJMBensonM, et al.Clinvar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res2018; 46: D1062–d1067.
51.
GuoYYangTLLiuYZ, et al.Mitochondria-wide association study of common variants in osteoporosis. Ann Hum Genet2011; 75: 569–574.
52.
van der WaltJMNicodemusKKMartinER, et al.Mitochondrial polymorphisms significantly reduce the risk of Parkinson disease. Am J Hum Genet2003; 72: 804–811.
53.
CottrellDABorthwickGMJohnsonMA, et al.The role of cytochrome c oxidase deficient hippocampal neurones in Alzheimer's disease. Neuropathol Appl Neurobiol2002; 28: 390–396.
54.
KemnaREKueckPJHoneaR, et al.Mitochondrial DNA affects tau phosphorylation in aging and Alzheimer's disease. Alzheimers Dement2025; 21: e70390.
55.
TongTZhuCFarrellJJ, et al.Blood-derived mitochondrial DNA copy number is associated with Alzheimer disease, Alzheimer-related biomarkers and serum metabolites. Alzheimers Res Ther2024; 16: 234.
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