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

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 disease. 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.

DOI: 10.1038/nature11283

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@article{Jnsson2012AMI, title={A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.}, author={Thorl{\'a}kur J{\'o}nsson and Jasvinder K Atwal and Stacy Steinberg and J{\'o}n Snaedal and Palmi V. Jonsson and Sigurbjorn Bjornsson and Hreinn Stefansson and Patrick Sulem and Daniel Fannar Gudbjartsson and Janice Maloney and Kwame Hoyte and Amy Gustafson and Yichin Liu and Yanmei Lu and Tushar Bhangale and Robert R. Graham and Johanna Huttenlocher and Gyda Bjornsdottir and Ole A. Andreassen and Erik J{\"{o}nsson and Aarno V Palotie and Timothy W. Behrens and Olafur Th Magnusson and Augustine Kong and Unnur Thorsteinsdottir and Ryan J. Watts and K{\'a}ri Stef{\'a}nsson}, journal={Nature}, year={2012}, volume={488 7409}, pages={96-9} }