CoChat
Sign Up
Cited by 10Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsTelomeres, Telomerase, and Senescence

Evaluating genomic signatures of aging in brain tissue as it relates to Alzheimer’s disease

Open access
Lynch, Megan T., Taub, Margaret A., Farfel, Jose M., Yang, Jingyun, Abadir, Peter, De Jager, Philip L., Grodstein, Francine, Bennett, David A. +1 more·2023·Scientific Reports
DOI 10.1038/s41598-023-41400-1PMC PMC10484923
Open this paper in CoChat — free accountOpen PDF

Abstract

Telomere length (TL) attrition, epigenetic age acceleration, and mitochondrial DNA copy number (mtDNAcn) decline are established hallmarks of aging. Each has been individually associated with Alzheimer’s dementia, cognitive function, and pathologic Alzheimer’s disease (AD). Epigenetic age and mtDNAcn have been studied in brain tissue directly but prior work on TL in brain is limited to small sample sizes and most studies have examined leukocyte TL. Importantly, TL, epigenetic age clocks, and mtDNAcn have not been studied jointly in brain tissue from an AD cohort. We examined dorsolateral prefrontal cortex (DLPFC) tissue from N = 367 participants of the Religious Orders Study (ROS) or the Rush Memory and Aging Project (MAP). TL and mtDNAcn were estimated from whole genome sequencing (WGS) data and cortical clock age was computed on 347 CpG sites. We examined dementia, MCI, and level of and change in cognition, pathologic AD, and three quantitative AD traits, as well as measures of other neurodegenerative diseases and cerebrovascular diseases (CVD). We previously showed that mtDNAcn from DLPFC brain tissue was associated with clinical and pathologic features of AD. Here, we show that those associations are independent of TL. We found TL to be associated with β-amyloid levels (beta = − 0.15, p = 0.023), hippocampal sclerosis (OR = 0.56, p = 0.0015) and cerebral atherosclerosis (OR = 1.44, p = 0.0007). We found strong associations between mtDNAcn and clinical measures of AD. The strongest associations with pathologic measures of AD were with cortical clock and there were associations of mtDNAcn with global AD pathology and tau tangles. Of the other pathologic traits, mtDNAcn was associated with hippocampal sclerosis, macroscopic infarctions and CAA and cortical clock was associated with Lewy bodies. Multi-modal age acceleration, accelerated aging on both mtDNAcn and cortical clock, had greater effect size than a single measure alone. These findings highlight for the first time that age acceleration determined on multiple genomic measures, mtDNAcn and cortical clock may have a larger effect on AD/AD related disorders (ADRD) pathogenesis than single measures.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41598-023-41400-1

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Telomere length reflects chromosome-end maintenance and accumulated cellular stress; mitochondrial DNA abundance or integrity reflects aspects of mitochondrial biology; and DNA methylation signatures capture tissue-, cell- and algorithm-specific epigenetic variation.

    “Telomere length reflects chromosome-end maintenance and accumulated cellular stress; mitochondrial DNA (mtDNA) abundance or integrity reflects aspects of mitochondrial biology; and DNA methylation signatures capture tissue-, cell- and algorithm-specific epigenetic variation [119,120].”

    From Placental Pathophysiology and Developmental Programming of Adult Cardiometabolic Risk: A Narrative Review of Pregnancy Exposures (2026) · cites this paper as [120]

    Split into 3 atoms — 1 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 68 · Cited by 10

Research works printed but not linked: 63

  1. [1]Rose MR Rose Evolutionary biology of aging 1991 Oxford University Press
  2. [2]Kennedy BK Geroscience: Linking aging to chronic disease Cell 2014 159 709 713 10.1016/j.cell.2014.10.039 25417146 PMC4852871 · DOI · Paper page
  3. [3]Johnson TE Recent results: Biomarkers of aging Exp. Gerontol. 2006 41 1243 1246 10.1016/j.exger.2006.09.006 17071038 · DOI · Paper page
  4. [4]López-Otín C Blasco MA Partridge L Serrano M Kroemer G The hallmarks of aging Cell 2013 153 1194 1217 10.1016/j.cell.2013.05.039 23746838 PMC3836174 · DOI · Paper page
  5. [5]Wang Y Brinton RD Triad of risk for late onset Alzheimer's: Mitochondrial haplotype, APOE genotype and chromosomal sex Front. Aging Neurosci. 2016 8 232 10.3389/fnagi.2016.00232 27757081 PMC5047907 · DOI
  6. [7]Area-Gomez E Guardia-Laguarta C Schon EA Przedborski S Mitochondria, OxPhos, and neurodegeneration: Cells are not just running out of gas J. Clin. Investig. 2019 129 34 45 10.1172/JCI120848 30601141 PMC6307938 · DOI
  7. [8]Stewart JB Chinnery PF Extreme heterogeneity of human mitochondrial DNA from organelles to populations Nat. Rev. Genet. 2021 22 106 118 10.1038/s41576-020-00284-x 32989265 · DOI
  8. [9]Larsson N Somatic Mitochondrial DNA mutations in mammalian aging Annu. Rev. Biochem. 2010 79 683 706 10.1146/annurev-biochem-060408-093701 20350166 · DOI
  9. [10]Rice AC Mitochondrial DNA copy numbers in pyramidal neurons are decreased and mitochondrial biogenesis transcriptome signaling is disrupted in Alzheimer's disease hippocampi J. Alzheimers Dis. 2014 40 319 330 10.3233/JAD-131715 24448779 · DOI
  10. [11]Rodríguez-Santiago B Casademont J Nunes V Is mitochondrial DNA depletion involved in Alzheimer's disease? Eur. J. Hum. Genetics: EJHG 2001 9 279 285 10.1038/sj.ejhg.5200629 11313772 · DOI · Paper page
  11. [12]Wei W Mitochondrial DNA point mutations and relative copy number in 1363 disease and control human brains Acta Neuropathol. Commun. 2017 5 13 10.1186/s40478-016-0404-6 28153046 PMC5290662 · DOI
  12. [14]Marioni RE The epigenetic clock is correlated with physical and cognitive fitness in the Lothian Birth Cohort 1936 Int. J. Epidemiol. 2015 44 1388 1396 10.1093/ije/dyu277 25617346 PMC4588858 · DOI
  13. [16]Smith AR Parallel profiling of DNA methylation and hydroxymethylation highlights neuropathology-associated epigenetic variation in Alzheimer's disease Clin. Epigenet. 2019 11 52 10.1186/s13148-019-0636-y PMC6429761 30898171 · DOI
  14. [18]Lardenoije R Alzheimer's disease-associated (hydroxy)methylomic changes in the brain and blood Clin. Epigenet. 2019 11 164 10.1186/s13148-019-0755-5 PMC6880587 31775875 · DOI
  15. [19]Yu L Association of brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease JAMA Neurol. 2014 72 15 24 10.1001/jamaneurol.2014.3049 PMC4344367 25365775 · DOI · Paper page
  16. [20]Smith RG A meta-analysis of epigenome-wide association studies in Alzheimer's disease highlights novel differentially methylated loci across cortex Nat. Commun. 2021 12 3517 10.1038/s41467-021-23243-4 34112773 PMC8192929 · DOI
  17. [22]Levine ME An epigenetic biomarker of aging for lifespan and healthspan Aging 2018 10 573 10.18632/aging.101414 29676998 PMC5940111 · DOI · Paper page
  18. [23]Nudelman KNH Telomere shortening in the Alzheimer's disease neuroimaging initiative cohort J. Alzheimers Dis. 2019 71 33 43 10.3233/JAD-190010 31322561 PMC7481955 · DOI
  19. [25]Scheller Madrid A Observational and genetic studies of short telomeres and Alzheimer’s disease in 67,000 and 152,000 individuals: A Mendelian randomization study Eur. J. Epidemiol. 2019 35 147 156 10.1007/s10654-019-00563-w 31564046 · DOI
  20. [26]Fani L Telomere length and the risk of Alzheimer's disease: The Rotterdam study J. Alzheimers Dis. 2020 73 707 714 10.3233/JAD-190759 31839608 PMC7029372 · DOI
  21. [27]Mahoney ER Telomere length associations with cognition depend on Alzheimer's disease biomarkers Alzheimer Dementia Transl. Res. Clin. Interv. 2019 5 883 890 10.1016/j.trci.2019.11.003 PMC6926345 31890852 · DOI
  22. [28]Scarabino D Broggio E Gambina G Corbo RM Leukocyte telomere length in mild cognitive impairment and Alzheimer's disease patients Exp. Gerontol. 2017 98 143 147 10.1016/j.exger.2017.08.025 28827085 · DOI
  23. [29]Fani L Telomere length and the risk of Alzheimer's disease: The Rotterdam study J. Alzheimer Dis. 2020 73 707 714 10.3233/JAD-190759 PMC7029372 31839608 · DOI
  24. [30]Nudelman KNH Telomere shortening in the Alzheimer’s disease neuroimaging initiative cohort JAD 2019 71 33 10.3233/JAD-190010 31322561 PMC7481955 · DOI
  25. [31]Roberts RO Short and long telomeres increase risk of amnestic mild cognitive impairment Mech. Ageing Dev. 2014 141–142 64 69 10.1016/j.mad.2014.10.002 25454987 PMC4310802 · DOI
  26. [32]Thomas P O’Callaghan NJ Fenech M Telomere length in white blood cells, buccal cells and brain tissue and its variation with ageing and Alzheimer's disease Mech. Ageing Dev. 2008 129 183 190 10.1016/j.mad.2007.12.004 18242664 · DOI
  27. [33]Lukens JN Van Deerlin V Clark CM Xie SX Johnson FB Comparisons of telomere lengths in peripheral blood and cerebellum in Alzheimer's disease Alzheimers Dement. 2009 5 463 469 10.1016/j.jalz.2009.05.666 19896585 PMC2859316 · DOI
  28. [34]Klein H Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain Mol. Neurodegener. 2021 16 1 17 10.1186/s13024-021-00495-8 34742335 PMC8572491 · DOI
  29. [35]Shireby GL Recalibrating the epigenetic clock: Implications for assessing biological age in the human cortex Brain 2020 143 3763 3775 10.1093/brain/awaa334 33300551 PMC7805794 · DOI
  30. [36]Grodstein F The association of epigenetic clocks in brain tissue with brain pathologies and common aging phenotypes Neurobiol. Dis. 2021 157 105428 10.1016/j.nbd.2021.105428 34153464 PMC8373772 · DOI
  31. [37]Bennett DA Religious orders study and rush memory and aging project J. Alzheimers Dis. 2018 64 S161 S189 10.3233/JAD-179939 29865057 PMC6380522 · DOI · Paper page
  32. [38]Bennett DA Schneider JA Arvanitakis Z Wilson RS Overview and findings from the religious orders study Curr. Alzheimer Res. 2012 9 628 645 10.2174/156720512801322573 22471860 PMC3409291 · DOI
  33. [39]Bennett DA Overview and findings from the rush memory and aging project Curr. Alzheimer Res. 2012 9 646 663 10.2174/156720512801322663 22471867 PMC3439198 · DOI
  34. [40]Schneider JA Arvanitakis Z Bang W Bennett DA Mixed brain pathologies account for most dementia cases in community-dwelling older persons Neurology 2007 69 2197 2204 10.1212/01.wnl.0000271090.28148.24 17568013 · DOI · Paper page
  35. [41]De Jager PL A genome-wide scan for common variants affecting the rate of age-related cognitive decline Neurobiol. Aging 2012 33 1017 e1 1017.e15 22054870 PMC3307898
  36. [43]Hyman B Trojanowski J Editorial on consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease J. Neuropathol. Exp. Neurol. 1997 56 1095 1097 10.1097/00005072-199710000-00002 9329452 · DOI · Paper page
  37. [45]Wilson RS Arnold SE Schneider JA Tang Y Bennett DA The relationship between cerebral Alzheimer’s disease pathology and odour identification in old age J. Neurol. Neurosurg. Psychiatry 2007 78 30 35 10.1136/jnnp.2006.099721 17012338 PMC2117790 · DOI
  38. [46]Nag S TDP-43 pathology and memory impairment in elders without pathologic diagnoses of AD or FTLD Neurology 2017 88 653 660 10.1212/WNL.0000000000003610 28087828 PMC5317379 · DOI
  39. [47]Schneider JA Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodies Brain 2012 135 3005 3014 10.1093/brain/aws234 23065790 PMC3470712 · DOI · Paper page
  40. [48]Nag S Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease Ann. Neurol. 2015 77 942 952 10.1002/ana.24388 25707479 PMC4447563 · DOI · Paper page
  41. [49]Arvanitakis Z Leurgans SE Barnes LL Bennett DA Schneider JA Microinfarct pathology, dementia, and cognitive systems Stroke 2011 1970 42 722 727 10.1161/STROKEAHA.110.595082 PMC3042494 21212395 · DOI · Paper page
  42. [50]Schneider JA The apolipoprotein E epsilon4 allele increases the odds of chronic cerebral infarction [corrected] detected at autopsy in older persons Stroke 2005 1970 36 954 959 10.1161/01.STR.0000160747.27470.2a 15774818 · DOI
  43. [51]Boyle P Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons Neurology 2015 85 1930 1936 10.1212/WNL.0000000000002175 26537052 PMC4664125 · DOI · Paper page
  44. [52]Love S Development, appraisal, validation and implementation of a consensus protocol for the assessment of cerebral amyloid angiopathy in post-mortem brain tissue Am. J. Neurodegener. Dis. 2014 3 19 32 24754000 PMC3986608
  45. [53]Arvanitakis Z The Relationship of Cerebral Vessel Pathology to Brain Microinfarcts Brain Pathol. (Zurich, Switzerland) 2017 27 77 85 10.1111/bpa.12365 PMC4974145 26844934 · DOI
  46. [54]Buchman AS Leurgans SE Nag S Bennett DA Schneider JA Cerebrovascular disease pathology and parkinsonian signs in old age Stroke 2011 1970 42 3183 3189 10.1161/STROKEAHA.111.623462 PMC3202031 21885844 · DOI · Paper page
  47. [55]De Jager PL A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research Sci. Data 2018 5 180142 10.1038/sdata.2018.142 30084846 PMC6080491 · DOI · Paper page
  48. [56]Ding Z Mangino M Aviv A Spector T Durbin R Estimating telomere length from whole genome sequence data Nucleic Acids Res 2014 42 e75 10.1093/nar/gku181 24609383 PMC4027178 · DOI
  49. [57]Conomos MP Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed Cell Genom. 2022 2 100084 10.1016/j.xgen.2021.100084 35530816 PMC9075703 · DOI
  50. [58]Zhong Y Wan Y Pang K Chow LML Liu Z Digital sorting of complex tissues for cell type-specific gene expression profiles BMC Bioinf. 2013 14 89 10.1186/1471-2105-14-89 PMC3626856 23497278 · DOI
  51. [59]Wang X Deciphering cellular transcriptional alterations in Alzheimer's disease brains Mol. Neurodegener. 2020 15 38 10.1186/s13024-020-00392-6 32660529 PMC7359236 · DOI
  52. [61]Bennett DA de Jager PL Leurgans SE Schneider JA Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles Neurology 2009 72 1495 1503 10.1212/WNL.0b013e3181a2e87d 19398704 PMC2677477 · DOI · Paper page
  53. [62]Farfel JM Alzheimer’s disease frequency peaks in the tenth decade and is lower afterwards Acta Neuropathol. Commun. 2019 7 104 10.1186/s40478-019-0752-0 31269985 PMC6609405 · DOI
  54. [63]Mengel-From J Mitochondrial DNA copy number in peripheral blood cells declines with age and is associated with general health among elderly Hum. Genet. 2014 133 1149 1159 10.1007/s00439-014-1458-9 24902542 PMC4127366 · DOI
  55. [64]Rausser S Mitochondrial phenotypes in purified human immune cell subtypes and cell mixtures eLife 2021 10 e70899 10.7554/eLife.70899 34698636 PMC8612706 · DOI
  56. [65]D'Erchia AM Tissue-specific mtDNA abundance from exome data and its correlation with mitochondrial transcription, mass and respiratory activity Mitochondrion 2015 20 13 21 10.1016/j.mito.2014.10.005 25446395 · DOI · Paper page
  57. [66]Kane AE Sinclair DA Epigenetic changes during aging and their reprogramming potential Crit. Rev. Biochem. Mol. Biol. 2019 54 61 83 10.1080/10409238.2019.1570075 30822165 PMC6424622 · DOI · Paper page
  58. [67]Kim B Integrative analysis of DNA methylation and gene expression identifies genes associated with biological aging in Alzheimer's disease Alzheimer's Dement. Diagn. Assess. Dis. Monit. 2022 14 e12354 PMC9489162 36187194
  59. [68]Tomita K Changes in telomere length with aging in human neurons and glial cells revealed by quantitative fluorescence in situ hybridization analysis Geriatr. Gerontol. Int. 2018 18 1507 1512 10.1111/ggi.13500 30095207 · DOI
  60. [69]Nakamura K Telomeric DNA length in cerebral gray and white matter is associated with longevity in individuals aged 70 years or older Exp. Gerontol. 2007 42 944 950 10.1016/j.exger.2007.05.003 17606349 · DOI
  61. [70]Demanelis K Determinants of telomere length across human tissues Science 2020 369 eaaz6876 10.1126/science.aaz6876 32913074 PMC8108546 · DOI · Paper page
  62. [71]Gardner M Gender and telomere length: Systematic review and meta-analysis Exp. Gerontol. 2014 51 15 27 10.1016/j.exger.2013.12.004 24365661 PMC4523138 · DOI
  63. [72]Brown L Needham B Ailshire J Telomere length among older U.S. adults: Differences by race/ethnicity, gender, and age J. Aging Health 2017 29 1350 1366 10.1177/0898264316661390 27469599 PMC5272874 · DOI

Authors
Lynch, M. T., Taub, M. A., Farfel, J. M., Yang, J., Abadir, P., De Jager, P. L., Grodstein, F., Bennett, D. A., & Mathias, R. A.
Affiliations
  • Johns Hopkins University (US)
  • Rush University Medical Center (US)
Corresponding author
Mathias, Rasika A.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2023-09-07
Volume
13
Issue
1
Pages
14747-14747
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-023-41400-1
PMC
PMC10484923
OpenAlex
W4386496318
Cited by
10
References
68
Citations by year
2026: 4 · 2025: 2 · 2024: 4
FWCI
2.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (AG 058527, P30AG10161, P30AG72975, T32 AG 058527, R01 AG69904, R01AG15819, R01AG17917, U01AG46152, U01AG61356)
  • RAM is the Sarah Miller Coulson Family Human Aging Project Scholar. The Johns Hopkins Human Aging Project: https://hap.jhu.edu/
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
Alzheimer's disease, telomere length, epigenetic age acceleration, mitochondrial DNA copy number, brain aging, dorsolateral prefrontal cortex, accelerated aging, amyloid-beta, hippocampal sclerosis, cerebral atherosclerosis, tau tangles, Lewy bodies, cerebrovascular disease, cognitive impairment, Religious Orders Study, Rush Memory and Aging Project
MeSH terms
Hippocampal Sclerosis, Aging, Alzheimer Disease, Brain, DNA, Mitochondrial, Humans, Genomics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review