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

被引：1247

作者：

Jonsson, Thorlakur ^{[1
]}

Atwal, Jasvinder K. ^{[2
]}

Steinberg, Stacy ^{[1
]}

Snaedal, Jon ^{[3
]}

Jonsson, Palmi V. ^{[3
,9
]}

Bjornsson, Sigurbjorn ^{[3
]}

Stefansson, Hreinn ^{[1
]}

Sulem, Patrick ^{[1
]}

Gudbjartsson, Daniel ^{[1
]}

Maloney, Janice ^{[2
]}

Hoyte, Kwame ^{[2
]}

Gustafson, Amy ^{[2
]}

Liu, Yichin ^{[2
]}

Lu, Yanmei ^{[2
]}

Bhangale, Tushar ^{[2
]}

Graham, Robert R. ^{[2
]}

Huttenlocher, Johanna ^{[1
,4
]}

Bjornsdottir, Gyda ^{[1
]}

Andreassen, Ole A. ^{[5
,6
]}

Jonsson, Erik G. ^{[7
]}

Palotie, Aarno ^{[8
]}

Behrens, Timothy W. ^{[2
]}

Magnusson, Olafur T. ^{[1
]}

Kong, Augustine ^{[1
]}

Thorsteinsdottir, Unnur ^{[1
,9
]}

Watts, Ryan J. ^{[2
]}

Stefansson, Kari ^{[1
,9
]}

机构：

[1] deCODE Genet, IS-101 Reykjavik, Iceland

[2] Genentech Inc, San Francisco, CA 94080 USA

[3] Landspitali Univ Hosp, Dept Geriatr, IS-101 Reykjavik, Iceland

[4] Inst Human Genet, Dept Med Genet, D-72026 Tubingen, Germany

[5] Univ Oslo, Ulleval Univ Hosp, Dept Psychiat, N-0407 Oslo, Norway

[6] Univ Oslo, Inst Psychiat, N-0407 Oslo, Norway

[7] Karolinska Hosp & Inst, HUBIN Project, Dept Clin Neurosci, SE-17176 Stockholm, Sweden

[8] Univ Helsinki, Dept Med Genet, FIN-00014 Helsinki, Finland

[9] Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland

来源：

NATURE | 2012年 / 488卷 / 7409期

关键词：

AMYLOID PRECURSOR PROTEIN; BETA-SECRETASE; IDENTIFICATION; PURIFICATION; PREVALENCE; IMPUTATION; DEMENTIA; CLEAVAGE; GENE; BACE;

D O I：

10.1038/nature11283

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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(1-4). 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-beta 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 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'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's disease, the two may be mediated through the same or similar mechanisms.

引用

页码：96 / 99

页数：4

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