A mutation in APP protects against Alzheimer%26apos;s disease and age-related cognitive decline

作者：Jonsson Thorlakur; Atwal Jasvinder K; Steinberg Stacy; Snaedal Jon; Jonsson Palmi V; Bjornsson Sigurbjorn; Stefansson Hreinn; Sulem Patrick; Gudbjartsson Daniel; Maloney Janice; Hoyte Kwame; Gustafson Amy; Liu Yichin; Lu Yanmei; Bhangale Tushar; Graham Robert R; Huttenlocher Johanna; Bjornsdottir Gyda; Andreassen Ole A; Jonsson Erik G; Palotie Aarno; Behrens Timothy W; Magnusson Olafur T; Kong Augustine; Thorsteinsdottir Unnur; Watts Ryan J; Stefansson Kari^*

来源：Nature, 2012, 488(7409): 96-99.

DOI：10.1038/nature11283

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%26apos;s disease(1-4). The age-specific prevalence of Alzheimer%26apos;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-beta precursor protein (APP) gene with a significant effect on the risk of Alzheimer%26apos;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%26apos;s disease and cognitive decline in the elderly without Alzheimer%26apos;s disease. This substitution is adjacent to the aspartyl protease beta-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%26apos;s disease provides proof of principle for the hypothesis that reducing the beta-cleavage of APP may protect against the disease. Furthermore, as the A673T allele also protects against cognitive decline in the elderly without Alzheimer%26apos;s disease, the two may be mediated through the same or similar mechanisms.

• 出版日期2012-8-2