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Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease
Theuns J, Brouwers N, Engelborghs S, Sleegers K, Bogaerts V, Corsmit E, De Pooter T, van Duijn CM et al.. American journal of human genetics, 2006-04-10
Topic: Amyloid, tau and blood-test diagnosis
Genetic variations in promoter sequences that alter gene expression play a prominent role in increasing susceptibility to complex diseases. Also, expression levels of APP are essentially regulated by its core promoter and 5' upstream regulatory region and correlate with amyloid beta levels in Alzheimer disease (AD) brains. Here, we systematically sequenced the proximal promoter (-766/+204) and two functional distal regions (-2634/-2159 and -2096/-1563) of APP in two independent AD series with onset ages A, -369C-->G, and -534G-->A) identified only in patients with AD showed, in vitro, a nearly twofold neuron-specific increase in APP transcriptional activity, similar to what is expected from triplication of APP in Down syndrome. These mutations either abolished (AP-2 and HES-1) or created (Oct1) transcription-factor binding sites involved in the development and differentiation of neuronal systems. Also, two of these clustered in the 200-bp region (-540/-340) of the APP promoter that showed the highest degree of species conservation. The present study provides evidence that APP-promoter mutations that significantly increase APP expression levels are associated with AD.
Key findings
- The present study provides evidence that APP-promoter mutations that significantly increase APP expression levels are associated with AD.
Why it matters
This genetic study found rare APP promoter mutations in people with Alzheimer disease that roughly doubled APP transcriptional activity in vitro, similar to the effect of an extra APP copy in Down syndrome. It provides evidence of a genetic risk mechanism and reports no treatment or cure.
Study details
- Evidence strengthLow
How this study scored 47/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (American journal of human genetics) |
| Journal's citation record | 3 / 4 | The American Journal of Human Genetics: journal h-index 385 (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 | 2006 — older than 20 years, still counted |
| 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) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 188 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 8.5 citations a year over 22 year(s) since 2006 |
| Impact for its field and year | 4 / 6 | Cited 10.0× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 12 other studies in this library |
| Still being cited | 1 / 4 | Cited 9 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Christine Van Broeckhoven: h-index 140 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Erasmus MC: institution h-index 1,321 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 5 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 16685645) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 47 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1086/504044
- PubMed: 16685645
- Original source →
- Free full text: The American Journal of Human Genetics →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Theuns, J., Brouwers, N., Engelborghs, S., Sleegers, K., Bogaerts, V., Corsmit, E., et al. (2006). Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. American journal of human genetics. https://doi.org/10.1086/504044
Vancouver
Theuns J, Brouwers N, Engelborghs S, Sleegers K, Bogaerts V, Corsmit E, et al. Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. American journal of human genetics. 2006. doi:10.1086/504044. PMID: 16685645.
BibTeX
@article{theuns2006-16685645,
author = {Theuns, J. and Brouwers, N. and Engelborghs, S. and Sleegers, K. and Bogaerts, V. and Corsmit, E. and De Pooter, T. and van Duijn, C. M. and others},
title = {{Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease}},
journal = {American journal of human genetics},
year = {2006},
doi = {10.1086/504044},
pmid = {16685645},
url = {https://doi.org/10.1086/504044}
}
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