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Kidney function and risk of dementia: Observational study, meta-analysis, and two-sample mendelian randomization study

  • NEURO-EPIDEMIOLOGY
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Abstract

Whether impaired kidney function is associated with increased risk of developing dementia is unclear. We investigated the association between estimated glomerular filtration rate (eGFR) and dementia. Using a triangulation approach, we performed (1) a prospective study in 90,369 Danes from the Copenhagen General Population Study (CGPS), (2) a meta-analysis in 468,699 Scandinavians (including CGPS) and (3) a two-sample Mendelian randomization study in 218,792-1,004,040 Europeans using summary data from largest publicly available genome wide association studies (GWASs). During up to 15 years of follow-up (CGPS), 2,468 individuals developed dementia. Age and sex standardized percentile of eGFR below versus above the median conferred a multifactorially adjusted hazard ratio of 1.09 (95% confidence interval: 1.01–1.18). In meta-analysis, random-effects risk of dementia was 1.14 (1.06–1.22) for mildly decreased eGFR (60–90 mL/min/1.73 m2), 1.31 (0.92–1.87) for moderately decreased eGFR (30–59 mL/min/1.73 m2) and 1.91 (1.21–3.01) for severely decreased eGFR (< 30 mL/min/1.73 m2), compared to reference eGFR (> 90 mL/min/1.73 m2). Using directly comparable eGFR measures (log[eGFR] scaled to one standard deviation, as well as eGFR below versus above 60 mL/min/1.73 m2), we found no association with risk of dementia in observational CGPS or in Mendelian randomization analyses. In conclusion, impaired kidney function was associated with modestly increased risk of developing dementia. This was not supported by causal, genetic analyses using a Mendelian randomization approach. However, future stronger genetic instruments for kidney function and larger GWASs with more dementia cases, particularly for the vascular dementia subtype, warrant a re-evaluation of the causal hypothesis.

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Acknowledgements

We want to acknowledge the participants and investigators/consortia of the studies used here, namely: CGPS (Copenhagen General Population Study), FinnGen, ADSP (Alzheimer’s Disease Sequencing Project), IGAP (International Genomics of Alzheimer’s Project), PGC-ALZ (Psychiatric Genomics Consortium’s working group on Alzheimer’s disease), UKB (UK Biobank) and CKDGen.

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Authors and Affiliations

  1. Steno Diabetes Center Aarhus, Aarhus University Hospital, Palle Juul-Jensens Blvd. 11, Indgang A, Aarhus, Denmark

    Alisa D. Kjaergaard

  2. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200, Copenhagen, Denmark

    Christina Ellervik & Børge G. Nordestgaard

  3. Department of Data and Development, Sorø, Region Zealand, Denmark

    Christina Ellervik

  4. Department of Pathology, Harvard Medical School and Department of Laboratory Medicine, Boston Children’s Hospital, MA-02215, Boston, USA

    Christina Ellervik

  5. Department of Public Health, Aarhus University, Aarhus, Denmark

    Daniel R. Witte

  6. Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev and Gentofte, University of Copenhagen, Herlev, Denmark

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

  7. Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark

    Ruth Frikke-Schmidt

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  1. Alisa D. Kjaergaard
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Correspondence to Alisa D. Kjaergaard.

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Kjaergaard, A.D., Ellervik, C., Witte, D.R. et al. Kidney function and risk of dementia: Observational study, meta-analysis, and two-sample mendelian randomization study. Eur J Epidemiol 37, 1273–1284 (2022). https://doi.org/10.1007/s10654-022-00923-z

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