A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline

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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.

At a glance


  1. Cognition measured by CPS as a function of age.
    Figure 1: Cognition measured by CPS as a function of age.

    Shown are CPS scores of carriers (red symbols) and non-carriers (blue symbols) of A673T as a function of age. Each symbol represents the average CPS score of individuals at the respective age (in years). Error bars represent±1 standard error. The jagged appearance of the graph for A673T carriers is due to the relatively small number of data points (262 in total, representing 41 individuals, as compared to 23,831 data points representing 3,673 A673T non-carriers). Individuals with a diagnosis of Alzheimer’s disease were not included in the analysis.

  2. A673T reduces BACE1 cleavage of APP.
    Figure 2: A673T reduces BACE1 cleavage of APP.

    a, Western blot analysis of 293T cells transfected with wild-type (WT), A673T, A673V or K670N/M671L APP compared to GFP. Total cellular APP was compared to sAPPβ and sAPPα from cell supernatants. Note that sAPPβ is not detected from the K670N/M671L APP transfection as these mutations alter the epitope recognized by the anti-sAPPβ antibody. b, Immunoassay quantification of sAPPβ and sAPPα supernatants. c, d, ELISA quantification of Aβx–40 (c) and Aβx–42 (d) production from the same 293T transfected cells. *P0.01, **P0.005, ***P0.001 (two-tailed t-test, compared to wild-type APP); values represent mean±s.d. of three replicates. The experiment was repeated independently three times.

Change history

Corrected online 01 August 2012
A minor error relating to the rs63750847 variant in ref. 15 was corrected.


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Author information


  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


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 financial interests

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

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