Skip to main content

Observational and genetic studies of short telomeres and Alzheimer’s disease in 67,000 and 152,000 individuals: a Mendelian randomization study

European Journal of Epidemiology volume 35, pages 147–156 (2020)Cite this article

Abstract

Short telomeres might lead to increased risk of Alzheimer’s disease, but observational analyses have been inconclusive and potentially confounded by the strong association of both telomere length and risk of Alzheimer’s disease with age and adverse lifestyle. To circumvent this, analyses including single nucleotide polymorphisms associated with telomere length used in an instrumental variable analysis produces risk estimates likely free of distortions from reverse causation and of most confounding. We tested the hypothesis that short telomeres are associated with increased risk of Alzheimer’s disease, observationally and causal, genetically. Telomere length was measured in 66,567 individuals, and genotyped for rs2487999 in OBFC1, rs7726159 in TERT, and rs1317082 in TERC causing lifelong telomere shortening in 98,146 individuals from two Copenhagen studies. Genetic data on 54,162 individuals from the International Genomics of Alzheimer’s Project were also included. Observationally, multifactorially adjusted hazard ratio for Alzheimer’s disease was 1.02 (95% CI 1.00–1.03) per 200 base pair shorter telomeres. Telomere length was 335 base pairs shorter in individuals with 6 versus 0–1 alleles (p = 5 × 10−105). Genetically, odds ratio for Alzheimer’s disease was 1.08 (1.01–1.16) per 200 base pairs shorter telomeres. Similar results were found in strata of age and comorbidities. In comparative analyses, genetically predicted shorter telomeres were associated with increased risk of myocardial infarction, and with decreased risks of lung cancer and melanoma as previously reported. Short telomeres were associated observationally and causal, genetically with increased risk of Alzheimer’s disease. Telomere biology is therefore a potential pathway involved in the development of Alzheimer’s disease.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Abbott A. Dementia: a problem for our age. Nature. 2011;475(7355):S2–4. https://doi.org/10.1038/475S2a.

    Article  CAS  PubMed  Google Scholar 

  2. Prince M, Wimo A, Guerchet M, et al. World Alzheimer Report 2015—the global impact of Dementia: an analysis of prevalence, incidence, cost and trends. London: Alzheimer’s Disease International; 2015. p. 84.

    Google Scholar 

  3. Blackburn EH. Switching and signaling at the telomere. Cell. 2001;106(6):661–73. https://doi.org/10.1016/S0092-8674(01)00492-5.

    Article  CAS  PubMed  Google Scholar 

  4. Scheller Madrid A, Rode L, Nordestgaard BG, Bojesen SE. Short telomere length and ischemic heart disease: observational and genetic studies in 290 022 individuals. Clin Chem. 2016;62(8):1140–9. https://doi.org/10.1373/clinchem.2016.258566.

    Article  CAS  PubMed  Google Scholar 

  5. Rode L, Nordestgaard BG, Bojesen SE. Peripheral blood leukocyte telomere length and mortality among 64,637 individuals from the general population. J Natl Cancer Inst. 2015;107(6):djv074. https://doi.org/10.1093/jnci/djv074.

    Article  CAS  PubMed  Google Scholar 

  6. Rode L, Nordestgaard BG, Bojesen SE. Long telomeres and cancer risk among 95,568 individuals from the general population. Int J Epidemiol. 2016;45(5):1634–43. https://doi.org/10.1093/ije/dyw179.

    Article  PubMed  Google Scholar 

  7. Eitan E, Hutchison ER, Mattson MP. Telomere shortening in neurological disorders: an abundance of unanswered questions. Trends Neurosci. 2014;37(5):256–63. https://doi.org/10.1016/j.tins.2014.02.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Panossian LA, Porter VR, Valenzuela HF, et al. Telomere shortening in T cells correlates with Alzheimer’s disease status. Neurobiol Aging. 2003;24(1):77–84.

    Article  CAS  Google Scholar 

  9. Honig LS, Kang MS, Schupf N, Lee JH, Mayeux R. Association of shorter leukocyte telomere repeat length with dementia and mortality. Arch Neurol. 2012;69(10):1332–9. https://doi.org/10.1001/archneurol.2012.1541.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Zekry D, Herrmann FR, Irminger-Finger I, et al. Telomere length and ApoE polymorphism in mild cognitive impairment, degenerative and vascular dementia. J Neurol Sci. 2010;299(1–2):108–11. https://doi.org/10.1016/j.jns.2010.07.019.

    Article  CAS  PubMed  Google Scholar 

  11. Moverare-Skrtic S, Johansson P, Mattsson N, et al. Leukocyte telomere length (LTL) is reduced in stable mild cognitive impairment but low LTL is not associated with conversion to Alzheimer’s disease: a pilot study. Exp Gerontol. 2012;47(2):179–82. https://doi.org/10.1016/j.exger.2011.12.005.

    Article  CAS  PubMed  Google Scholar 

  12. Valdes AM, Deary IJ, Gardner J, et al. Leukocyte telomere length is associated with cognitive performance in healthy women. Neurobiol Aging. 2010;31(6):986–92. https://doi.org/10.1016/j.neurobiolaging.2008.07.012.

    Article  CAS  PubMed  Google Scholar 

  13. Forero DA, Gonzalez-Giraldo Y, Lopez-Quintero C, Castro-Vega LJ, Barreto GE, Perry G. Meta-analysis of telomere length in Alzheimer’s disease. J Gerontol A Biol Sci Med Sci. 2016;71(8):1069–73. https://doi.org/10.1093/gerona/glw053.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Jacobs EG, Epel ES, Lin J, Blackburn EH, Rasgon NL. Relationship between leukocyte telomere length, telomerase activity, and hippocampal volume in early aging. JAMA Neurol. 2014;71(7):921–3. https://doi.org/10.1001/jamaneurol.2014.870.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Valdes AM, Andrew T, Gardner JP, et al. Obesity, cigarette smoking, and telomere length in women. Lancet (London, England). 2005;366(9486):662–4. https://doi.org/10.1016/s0140-6736(05)66630-5.

    Article  CAS  Google Scholar 

  16. Crous-Bou M, Fung TT, Prescott J, et al. Mediterranean diet and telomere length in Nurses’ Health Study: population based cohort study. BMJ (Clin Res Ed). 2014;349:g6674. https://doi.org/10.1136/bmj.g6674.

    Article  CAS  Google Scholar 

  17. Norton S, Matthews FE, Barnes DE, Yaffe K, Brayne C. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol. 2014;13(8):788–94. https://doi.org/10.1016/s1474-4422(14)70136-x.

    Article  PubMed  Google Scholar 

  18. Bojesen SE. Telomeres and human health. J Intern Med. 2013;274(5):399–413. https://doi.org/10.1111/joim.12083.

    Article  CAS  PubMed  Google Scholar 

  19. Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45(12):1452–8. https://doi.org/10.1038/ng.2802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rasmussen KL, Tybjærg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma levels of apolipoprotein E and risk of dementia in the general population. Ann Neurol. 2015;77(2):301–11. https://doi.org/10.1002/ana.24326.

    Article  CAS  PubMed  Google Scholar 

  21. Nordestgaard LT, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Loss-of-function mutation in ABCA1 and risk of Alzheimer’s disease and cerebrovascular disease. Alzheimers Dement. 2015;11(12):1430–8. https://doi.org/10.1016/j.jalz.2015.04.006.

    Article  PubMed  Google Scholar 

  22. Afzal S, Tybjaerg-Hansen A, Jensen GB, Nordestgaard BG. Change in body mass index associated with lowest mortality in Denmark, 1976–2013. JAMA. 2016;315(18):1989–96. https://doi.org/10.1001/jama.2016.4666.

    Article  CAS  PubMed  Google Scholar 

  23. Rasmussen KL, Tybjaerg-Hansen A, Nordestgaard BG, Frikke-Schmidt R. Plasma apolipoprotein E levels and risk of dementia: a Mendelian randomization study of 106,562 individuals. Alzheimers Dement. 2018;14(1):71–80. https://doi.org/10.1016/j.jalz.2017.05.006.

    Article  PubMed  Google Scholar 

  24. Cawthon RM. Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucl Acids Res. 2009;37(3):e21. https://doi.org/10.1093/nar/gkn1027.

    Article  CAS  PubMed  Google Scholar 

  25. Weischer M, Bojesen SE, Cawthon RM, Freiberg JJ, Tybjaerg-Hansen A, Nordestgaard BG. Short telomere length, myocardial infarction, ischemic heart disease, and early death. Arterioscler Thromb Vasc Biol. 2012;32(3):822–9. https://doi.org/10.1161/ATVBAHA.111.237271.

    Article  CAS  PubMed  Google Scholar 

  26. Pooley KA, Bojesen SE, Weischer M, et al. A genome-wide association scan (GWAS) for mean telomere length within the COGS project: identified loci show little association with hormone-related cancer risk. Hum Mol Genet. 2013;22(24):5056–64. https://doi.org/10.1093/hmg/ddt355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ishikawa F. CST Complex and Telomere Maintenance. In: Hanaoka F, Sugasawa K, editors. DNA replication, recombination, and repair: molecular mechanisms and pathology. Tokyo: Springer Japan; 2016. p. 389–401.

    Chapter  Google Scholar 

  28. Didelez V, Meng S, Sheehan NA. Assumptions of IV methods for observational epidemiology. Stat Sci. 2010;25:22–40.

    Article  Google Scholar 

  29. Burgess S, Scott RA, Timpson NJ, Smith GD, Thompson SG, Consortium E-I. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol. 2015;30(7):543–52.

    Article  Google Scholar 

  30. Codd V, Nelson CP, Albrecht E, et al. Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet. 2013;45(4):422. https://doi.org/10.1038/ng.2528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Spiller W, Davies NM, Palmer TM. Software application profile: mrrobust—a tool for performing two-sample summary Mendelian randomization analyses. Int J Epidemiol. 2018. https://doi.org/10.1093/ije/dyy195.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Bowden J, Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44(2):512–25. https://doi.org/10.1093/ije/dyv080.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Bowden J, Smith G, Haycock PC, Burgess S. Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304–14. https://doi.org/10.1002/gepi.21965.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Sanderson SL, Simon AK. In aged primary T cells, mitochondrial stress contributes to telomere attrition measured by a novel imaging flow cytometry assay. Aging Cell. 2017;16(6):1234–43.

    Article  CAS  Google Scholar 

  35. Jaskelioff M, Muller FL, Paik J-H, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2010;469(7328):102–6. https://doi.org/10.1038/nature09603.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Cong Y, Shay JW. Actions of human telomerase beyond telomeres. Cell Res. 2008;18(7):725–32. https://doi.org/10.1038/cr.2008.74.

    Article  CAS  PubMed  Google Scholar 

  37. Rice C, Skordalakes E. Structure and function of the telomeric CST complex. Comput Struct Biotechnol J. 2016;14:161–7. https://doi.org/10.1016/j.csbj.2016.04.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lawlor DA, Harbord RM, Sterne JAC, Timpson N, Davey Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27(8):1133–63. https://doi.org/10.1002/sim.3034.

    Article  PubMed  Google Scholar 

  39. Varbo A, Benn M, Tybjaerg-Hansen A, Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013;61(4):427–36. https://doi.org/10.1016/j.jacc.2012.08.1026.

    Article  CAS  PubMed  Google Scholar 

  40. Swanson SA, Tiemeier H, Ikram AM, Hernán MA. Nature as a trialist&quest. Epidemiology. 2017;28(5):653–9. https://doi.org/10.1097/EDE.0000000000000699.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Zhan Y, Song C, Karlsson R, et al. Telomere length shortening and Alzheimer disease—a Mendelian randomization study. JAMA Neurol. 2015;72(10):1202–3. https://doi.org/10.1001/jamaneurol.2015.1513.

    Article  PubMed  Google Scholar 

  42. Phung TKT, Andersen BB, Høgh P, Kessing LV, Mortensen PB, Waldemar G. Validity of dementia diagnoses in the Danish hospital registers. Dement Geriatr Cogn Disord. 2007;24(3):220–8. https://doi.org/10.1159/000107084.

    Article  PubMed  Google Scholar 

  43. Lukens NJ, Deerlin V, Clark CM, Xie SX, Johnson BF. Comparisons of telomere lengths in peripheral blood and cerebellum in Alzheimer’s disease. Alzheimer’s Dement. 2009;5(6):463–9. https://doi.org/10.1016/j.jalz.2009.05.666.

    Article  CAS  Google Scholar 

  44. 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(4):183.

    Article  CAS  Google Scholar 

  45. Schwartz M, Shechter R. Systemic inflammatory cells fight off neurodegenerative disease. Nat Rev Neurol. 2010;6(7):405–10. https://doi.org/10.1038/nrneurol.2010.71.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Special thanks to laboratory technician Anja Jochumsen for assisting with the large-scale telomere length measurements. We are grateful to all the staff and participants of the Copenhagen City Heart Study and the Copenhagen General Population Study for their important contributions. We thank the International Genomics of Alzheimer’s Project (IGAP) for providing summary results data for these analyses. The investigators within IGAP contributed to the design and implementation of IGAP and/or provided data but did not participate in analysis or writing of this report. IGAP was made possible by the generous participation of the control subjects, the patients, and their families. The i–Select chips was funded by the French National Foundation on Alzheimer’s disease and related disorders. EADI was supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ Grant, Inserm, Institut Pasteur de Lille, Université de Lille 2 and the Lille University Hospital. GERAD was supported by the Medical Research Council (Grant No. 503480), Alzheimer’s Research UK (Grant No. 503176), the Wellcome Trust (Grant No. 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) Grant Nos. 01GI0102, 01GI0711, 01GI0420. CHARGE was partly supported by the NIH/NIA Grant R01 AG033193 and the NIA AG081220 and AGES contract N01–AG–12100, the NHLBI Grant R01 HL105756, the Icelandic Heart Association, and the Erasmus Medical Center and Erasmus University. ADGC was supported by the NIH/NIA Grants: U01 AG032984, U24 AG021886, U01 AG016976, and the Alzheimer’s Association Grant ADGC–10–196728. Stig E Bojesen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Alexander Scheller Madrid and Stig E. Bojesen conducted the data analyses. Alexander Scheller Madrid, Katrine L Rasmussen, Line Rode, Ruth Frikke-Schmidt, Børge G Nordestgaard, and Stig E. Bojesen are all responsible for the data analyses.

Funding

This work was supported by Chief Physician Johan Boserup and Lise Boserup’s Foundation, the Copenhagen County Foundation, the Danish Medical Research Council and Herlev Hospital, all of which are nonprofit/public organizations with no right to approve or disapprove of the work.

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev Ringvej 75, 2730, Herlev, Denmark

    Alexander Scheller Madrid, Katrine L. Rasmussen, Line Rode, Børge G. Nordestgaard & Stig E. Bojesen

  2. The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

    Katrine L. Rasmussen, Ruth Frikke-Schmidt, Børge G. Nordestgaard & Stig E. Bojesen

  3. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Ruth Frikke-Schmidt, Børge G. Nordestgaard & Stig E. Bojesen

  4. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Katrine L. Rasmussen & Ruth Frikke-Schmidt

  5. The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Frederiksberg, Denmark

    Børge G. Nordestgaard & Stig E. Bojesen

Authors
  1. Alexander Scheller Madrid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katrine L. Rasmussen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Line Rode
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ruth Frikke-Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Børge G. Nordestgaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stig E. Bojesen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stig E. Bojesen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 158 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Scheller Madrid, A., Rasmussen, K.L., Rode, L. et al. 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 35, 147–156 (2020). https://doi.org/10.1007/s10654-019-00563-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10654-019-00563-w

Keywords

  • Telomere length
  • Alzheimer’s disease
  • Causal association
  • Mendelian randomization
  • General population