A mutation in APP protects against Alzheimer's disease and age-related cognitive decline.
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.
deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.
Thorlakur
T
Jonsson
Jasvinder K
JK
Atwal
Stacy
S
Steinberg
Jon
J
Snaedal
Palmi V
PV
Jonsson
Sigurbjorn
S
Bjornsson
Hreinn
H
Stefansson
Patrick
P
Sulem
Daniel
D
Gudbjartsson
Janice
J
Maloney
Kwame
K
Hoyte
Amy
A
Gustafson
Yichin
Y
Liu
Yanmei
Y
Lu
Tushar
T
Bhangale
Robert R
RR
Graham
Johanna
J
Huttenlocher
Gyda
G
Bjornsdottir
Ole A
OA
Andreassen
Erik G
EG
Jönsson
Aarno
A
Palotie
Timothy W
TW
Behrens
Olafur T
OT
Magnusson
Augustine
A
Kong
Unnur
U
Thorsteinsdottir
Ryan J
RJ
Watts
Kari
K
Stefansson
D000375:Aging / Q000235:genetics*; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000235:genetics* / Q000503:physiopathology* / Q000517:prevention & control; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation / Q000235:genetics*; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human