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A mutation in APP protects against Alzheimer's disease and age-related cognitive decline
Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P et al.. Nature, 2012-08-01
Topic: Amyloid, tau and blood-test diagnosis
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.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Jonsson, T., Atwal, J. K., Steinberg, S., Snaedal, J., Jonsson, P. V., Bjornsson, S., et al. (2012). A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. https://doi.org/10.1038/nature11283
Vancouver
Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature. 2012. doi:10.1038/nature11283. PMID: 22801501.
BibTeX
@article{jonsson2012-22801501,
author = {Jonsson, T. and Atwal, J. K. and Steinberg, S. and Snaedal, J. and Jonsson, P. V. and Bjornsson, S. and Stefansson, H. and Sulem, P. and others},
title = {{A mutation in APP protects against Alzheimer's disease and age-related cognitive decline}},
journal = {Nature},
year = {2012},
doi = {10.1038/nature11283},
pmid = {22801501},
url = {https://doi.org/10.1038/nature11283}
}
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Key findings
- 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.
Why it matters
In whole-genome sequence data from 1,795 Icelanders, the authors report that a rare change in the APP gene, called A673T, "protects against Alzheimer's disease and cognitive decline in the elderly without Alzheimer's disease"; in lab experiments the change cut formation of amyloid-forming peptides by "approximately 40%". The authors present this as "proof of principle for the hypothesis that reducing the β-cleavage of APP may protect against the disease". The summary does not give the size of the protective effect or results from other populations, and this is a finding about an inherited gene variant, not a treatment.
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Study details
- Evidence strengthLow
How this study scored 61/100
Published in a top-tier journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature) |
| Journal's citation record | 4 / 4 | Nature: journal h-index 1,841 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2012 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 7 / 7 | Cited 1,744 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 109.0 citations a year over 16 year(s) since 2012 |
| Impact for its field and year | 6 / 6 | Cited 104.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 79 other studies in this library |
| Still being cited | 4 / 4 | Cited 220 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Kāri Stefánsson: h-index 227 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Karolinska Institutet: institution h-index 1,477 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 6 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 22801501) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 61 / 100 | — |
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