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

• Published in: Nature (London) Vol. 488; no. 7409; pp. 96 - 99
• Main Authors: 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., Jönsson, Erik G., Palotie, Aarno, Behrens, Timothy W., Magnusson, Olafur T., Kong, Augustine, Thorsteinsdottir, Unnur, Watts, Ryan J., Stefansson, Kari
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.08.2012; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/208/726/649; 631/378/1689/1283; Adult and adolescent clinical studies; Aging - genetics; Alleles; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer Disease - prevention & control; Alzheimer's disease; Amyloid beta-Protein Precursor - chemistry; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - metabolism; Biological and medical sciences; Cognition - physiology; Cognition disorders; Cognition Disorders - genetics; Cognition Disorders - physiopathology; Cognition Disorders - prevention & control; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Development and progression; Gene mutations; Genetic aspects; Genetic Predisposition to Disease; HEK293 Cells; Humanities and Social Sciences; Humans; letter; Medical sciences; Medicin och hälsovetenskap; multidisciplinary; Mutation - genetics; Neurology; Organic mental disorders. Neuropsychology; Physiological aspects; Plaque, Amyloid - genetics; Plaque, Amyloid - metabolism; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Science; Science (multidisciplinary); United States; Nervous system diseases; Prevalence; Alzheimer disease; Central nervous system disease; Degenerative disease; Mutation; Epidemiology; Amyloid precursor protein; Cerebral disorder
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature11283

A coding mutation in APP , the gene that encodes the amyloid-β precursor protein, is found to protect against Alzheimer’s disease and cognitive decline in the elderly without Alzheimer’s disease. 'Natural' protection against Alzheimer's disease Alzheimer's disease is characterized by the existence in the brain of amyloid plaques, which form as a consequence of proteolic cleavage of amyloid precursor protein (APP). By screening almost 2,000 genomes, Kari Stefansson and colleagues find a coding mutation in the APP gene that protects against Alzheimer's disease and cognitive decline in elderly people who lack symptoms of Alzheimer's disease. The mutation causes an approximately 40% reduction in the formation of amyloidogenic peptides in vitro . The strong protective effect of this mutation, which lies next to the aspartyl protease beta-site in APP, provides support for the hypothesis that reducing the beta-cleavage of APP may protect against Alzheimer's. The results also raise the possibility that Alzheimer's disease and cognitive decline in the elderly are mechanistically related. 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 , 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.