Topic: Amyloid, tau and blood-test diagnosis
Plain-language summary
APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.
What this study adds
Evidence grade: High
This is a pooled review of 4,203 participants. Because APOE ɛ4 "may mask effects of other loci," this study looked separately at people without ɛ4 and found a new genome-wide significant signal in a region of chromosome 17 near MAPT, the gene for tau protein, where one SNP (rs2732703) accounted for the whole signal. The same variants were linked to activity of the nearby KANSL1 gene, and more weakly MAPT, in brain tissue, and an early-stage analysis suggested APOE may interact with a TMEM106B variant previously tied to frontotemporal dementia.
Taken from this record’s own fields, not from reading the paper. The grade is assigned from the abstract’s wording; what that means.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Jun, G., Ibrahim-Verbaas, C. A., Vronskaya, M., Lambert, J. C., Chung, J., Naj, A. C., et al. (2016). A novel Alzheimer disease locus located near the gene encoding tau protein. Molecular psychiatry. https://doi.org/10.1038/mp.2015.23
Vancouver
Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert JC, Chung J, Naj AC, et al. A novel Alzheimer disease locus located near the gene encoding tau protein. Molecular psychiatry. 2016. doi:10.1038/mp.2015.23. PMID: 25778476.
BibTeX
@article{jun2016-25778476,
author = {Jun, G. and Ibrahim-Verbaas, C. A. and Vronskaya, M. and Lambert, J. C. and Chung, J. and Naj, A. C. and Kunkle, B. W. and Wang, L. S. and others},
title = {{A novel Alzheimer disease locus located near the gene encoding tau protein}},
journal = {Molecular psychiatry},
year = {2016},
doi = {10.1038/mp.2015.23},
pmid = {25778476},
url = {https://doi.org/10.1038/mp.2015.23}
}
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.
Key findings
- APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci.
- Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)).
- Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT.
- Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup.
- In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia.
Why it matters
Because APOE ɛ4 "may mask effects of other loci," this study looked separately at people without ɛ4 and found a new genome-wide significant signal in a region of chromosome 17 near MAPT, the gene for tau protein, where one SNP (rs2732703) accounted for the whole signal. The same variants were linked to activity of the nearby KANSL1 gene, and more weakly MAPT, in brain tissue, and an early-stage analysis suggested APOE may interact with a TMEM106B variant previously tied to frontotemporal dementia. The authors say the result needs replication in independent samples before the region's role is confirmed; it points to where to look, not to a treatment.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Study designmeta-analysis
- Participants4,203
- Evidence strengthHigh
How this study scored 79/100
Published in a leading specialty journal, and it is a meta-analysis pooling many studies. Scored zero for effect reported because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Molecular psychiatry) |
| Journal's citation record | 3 / 4 | Molecular Psychiatry: journal h-index 318 (OpenAlex, 2026-10-29) |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2016 — within 20 year(s) of the newest study here |
| Sample size | 3 / 4 | 4,203 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomized / blinded | 0 / 2 | A review of other studies — randomization is not credited here |
| Times cited | 5 / 7 | Cited 294 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 24.5 citations a year over 12 year(s) since 2016 |
| Impact for its field and year | 4 / 6 | Cited 17.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 25 other studies in this library |
| Still being cited | 3 / 4 | Cited 63 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Albert Hofman: h-index 193 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | University of Washington: institution h-index 3,540 (OpenAlex) |
| Multicenter collaboration | 3 / 3 | OpenAlex lists 75 institution(s) in 12 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 25778476) |
| Free to read | 2 / 2 | Free to read |
| Total | 79 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Related
Studies in the library that share something with this one. The line above each title says what.
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.
Later studies that cite this one
25 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.
Related studies in Genetics from nearby years
Also tagged “phosphorylated”
732 studies in the library carry the topic tag “phosphorylated”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 732 tagged studies.