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Abstract

The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about two-thirds of which are due to Alzheimer’s disease1,2,3,4. The age-specific prevalence of Alzheimer’s disease nearly doubles every 5 years after age 65, leading to a prevalence of greater than 25% in those over the age of 90 (ref. 3). Here, to search for low-frequency variants in the amyloid-β precursor protein (APP) gene with a significant effect on the risk of Alzheimer’s disease, we studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. We found a coding mutation (A673T) in the APP gene that protects against Alzheimer’s disease and cognitive decline in the elderly without Alzheimer’s disease. This substitution is adjacent to the aspartyl protease β-site in APP, and results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro. The strong protective effect of the A673T substitution against Alzheimer’s disease provides proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer’s disease, the two may be mediated through the same or similar mechanisms.

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Change history

  • 01 August 2012

    A minor error relating to the rs63750847 variant in ref. 15 was corrected.

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Acknowledgements

We would like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).

Author information

Affiliations

  1. deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland

    • Thorlakur Jonsson
    • , Stacy Steinberg
    • , Hreinn Stefansson
    • , Patrick Sulem
    • , Daniel Gudbjartsson
    • , Johanna Huttenlocher
    • , Gyda Bjornsdottir
    • , Olafur T. Magnusson
    • , Augustine Kong
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  2. Genentech, 1 DNA Way, South San Francisco, California 94080, USA

    • Jasvinder K. Atwal
    • , Janice Maloney
    • , Kwame Hoyte
    • , Amy Gustafson
    • , Yichin Liu
    • , Yanmei Lu
    • , Tushar Bhangale
    • , Robert R. Graham
    • , Timothy W. Behrens
    •  & Ryan J. Watts
  3. Landspitali University Hospital, Department of Geriatrics, 101 Reykjavik, Iceland

    • Jon Snaedal
    • , Palmi V. Jonsson
    •  & Sigurbjorn Bjornsson
  4. Department of Medical Genetics, Institute for Human Genetics, 72026 Tübingen, Germany

    • Johanna Huttenlocher
  5. Department of Psychiatry, Ullevål University Hospital and Institute of Psychiatry, University of Oslo, N-0407 Oslo, Norway

    • Ole A. Andreassen
  6. Department of Clinical Neuroscience, HUBIN project, Karolinska Institutet and Hospital, SE-171 76 Stockholm, Sweden

    • Erik G. Jönsson
  7. Department of Medical Genetics, University of Helsinki, 00014 Helsinki, Finland

    • Aarno Palotie
  8. University of Iceland, Faculty of Medicine, 101 Reykjavik, Iceland

    • Palmi V. Jonsson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson

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Contributions

The study was designed and results were interpreted by T.J., J.K.A., H.S., R.J.W. and K.S. Sequence data analysis was carried out by T.J., S.S., P.S., A.K., T.B., R.R.G., T.W.B. and D.G. Subject recruitment, phenotype analysis and biological material collection was organized and carried out by J.S., P.V.J., S.B., G.B., O.A.A., E.G.J. and A.P. Sequencing and genotyping was supervised by J.H., O.T.M. and U.T. Cell line experiments and BACE1 cleavage assays were carried out and analysed by J.K.A., J.M., K.H., Y. Lu, Y. Liu, A.G. and R.J.W. The paper was drafted by T.J., J.K.A., R.J.W. and K.S. All authors contributed to the final version of the paper.

Competing interests

Authors from deCODE and Genentech are employees of deCODE genetics, ehf and Genentech, respectively.

Corresponding author

Correspondence to Kari Stefansson.

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DOI

https://doi.org/10.1038/nature11283

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