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Amyloid, tau and risk of Alzheimer’s disease: a Mendelian randomization study

  • NEURO-EPIDEMIOLOGY
  • Published:
European Journal of Epidemiology Aims and scope Submit manuscript

Abstract

This study was carried out to assess the effect of amyloid and tau on Alzheimer’s disease using two-sample Mendelian randomization design. Genetic associations with plasma amyloid species (amyloid precursor protein, amyloid-like protein 2, serum amyloid P-component, amyloid beta peptide), cerebrospinal fluid (CSF) amyloid beta, total tau, and phosphorylated tau181 were extracted from the largest genome-wide association study (GWAS) available. Genetic associations with Alzheimer’s disease were obtained from a GWAS of proxy-cases based on family history of Alzheimer’s disease with 314,278 participants from the UK Biobank and a GWAS with clinically diagnosed Alzheimer’s disease from the International Genomics of Alzheimer’s Project (IGAP) with 21,982 cases and 41,944 controls. Estimates were obtained using inverse variance weighting with sensitivity analyses including MR-Egger, weighted median and MR-PRESSO. Presence of bias due to selective survival and competing risk was also considered. Plasma amyloid species, CSF total tau and phosphorylated tau181 were not associated with Alzheimer’s disease. For CSF Aβ42, no association was found using the proxy-cases but an inverse association was found after removing outliers with MR-PRESSO using IGAP. Higher genetically predicted (p < 1 × 10−5) plasma amyloid species, CSF total tau and phosphorylated tau181 (based on sample sizes ~ 3300) were not associated with Alzheimer’s disease using family history or clinically diagnosed cases while effects of CSF Aβ42 were inconsistent between the family history and IGAP GWAS.

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Acknowledgements

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/PERADES was supported by the Medical Research Council (Grant n° 503480), Alzheimer’s Research UK (Grant n° 503176), the Wellcome Trust (Grant n° 082604/2/07/Z) and German Federal Ministry of Education and Research (BMBF): Competence Network Dementia (CND) Grant n° 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. Data on family history Alzheimer’s disease summary statistics have been contributed by Centre for Cognitive Ageing and Cognitive Epidemiology at the University of Edinburgh and have been downloaded from http://www.ccace.ed.ac.uk/about-us. Data on age at recruitment have been contributed by UK Biobank Ben Neale files and have been downloaded from http://www.nealelab.is/uk-biobank.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 7 Sassoon Road, Pokfulam, Hong Kong SAR, China

    Chris Ho Ching Yeung, Kathleen Wen Din Lau, Shiu Lun Au Yeung & C. Mary Schooling

  2. Graduate School of Public Health and Health Policy, City University of New York, New York, USA

    C. Mary Schooling

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  1. Chris Ho Ching Yeung
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All authors designed the study and interpreted the results. CHCY conducted the analyses and wrote the first draft of the article with critical feedback and revision from CMS, SLAY and KL. All authors gave approval for the final version of the article for publication.

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Correspondence to C. Mary Schooling.

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Yeung, C.H.C., Lau, K.W.D., Au Yeung, S.L. et al. Amyloid, tau and risk of Alzheimer’s disease: a Mendelian randomization study. Eur J Epidemiol 36, 81–88 (2021). https://doi.org/10.1007/s10654-020-00683-8

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