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

  • NEURO-EPIDEMIOLOGY
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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.

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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.

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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

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  1. Alexander Scheller Madrid
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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

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