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Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk
Ebbert MTW, Boehme KL, Wadsworth ME, Staley LA, Alzheimer's Disease Neuroimaging Initiative, Alzheimer's Disease Genetics Consortium, Mukherjee S, Crane PK et al.. Alzheimer's & dementia : the journal of the Alzheimer's Association, 2015-10-09
Topic: Amyloid, tau and blood-test diagnosis
Introduction Ebbert et al. reported gene-gene interactions between rs11136000-rs670139 (CLU-MS4A4E) and rs3865444-rs670139 (CD33-MS4A4E). We evaluate these interactions in the largest data set for an epistasis study. Methods We tested interactions using 3837 cases and 4145 controls from Alzheimer's Disease Genetics Consortium using meta-analyses and permutation analyses. We repeated meta-analyses stratified by apolipoprotein E (APOE) ε4 status, estimated combined odds ratio (OR) and population attributable fraction (cPAF), and explored causal variants. Results Results support the CLU-MS4A4E interaction and a dominant effect. An association between CLU-MS4A4E and APOE ε4 negative status exists. The estimated synergy factor, OR, and cPAF for rs11136000-rs670139 are 2.23, 2.45, and 8.0, respectively. We identified potential causal variants. Discussion We replicated the CLU-MS4A4E interaction in a large case-control series and observed APOE ε4 and possible dominant effect. The CLU-MS4A4E OR is higher than any Alzheimer's disease locus except APOE ε4, APP, and TREM2. We estimated an 8% decrease in Alzheimer's disease incidence without CLU-MS4A4E risk alleles and identified potential causal variants.
Key findings
- Results Results support the CLU-MS4A4E interaction and a dominant effect.
Why it matters
Using 3837 cases and 4145 controls, this study confirmed that variants in the CLU and MS4A4E genes interact to raise Alzheimer's risk, especially in people without APOE ε4. The authors estimate an 8% decrease in Alzheimer's incidence without these risk alleles and identify possible causal variants. This is a statistical genetic estimate, pointing to gene combinations worth further study.
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Study details
- Study designmeta-analysis
- Evidence strengthHigh
How this study scored 54/100
Published in a leading specialty journal, and it is a meta-analysis pooling many studies. Scored zero for sample size, effect reported and studied in people because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Alzheimer's & dementia : the journal of the Alzheimer's Association) |
| Journal's citation record | 2 / 4 | Alzheimer s & Dementia: journal h-index 228 (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 | 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 | A review of other studies — randomisation is not credited here |
| Times cited | 3 / 7 | Cited 21 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.8 citations a year over 12 year(s) since 2016 |
| Impact for its field and year | 2 / 6 | Cited 2.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 1 other studies in this library |
| Still being cited | 0 / 4 | Cited 2 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author John S. K. Kauwe: h-index 43 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | University of Washington: institution h-index 3,540 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 26449541) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 54 / 100 | — |
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Read the original
- DOI: 10.1016/j.jalz.2015.08.163
- PubMed: 26449541
- Original source →
- Free full text: bioRxiv (Cold Spring Harbor Laboratory) →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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APA 7th
Ebbert, M. T. W., Boehme, K. L., Wadsworth, M. E., Staley, L. A., Alzheimer's Disease Neuroimaging Initiative, Alzheimer's Disease Genetics Consortium, et al. (2016). Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk. Alzheimer's & dementia : the journal of the Alzheimer's Association. https://doi.org/10.1016/j.jalz.2015.08.163
Vancouver
Ebbert MTW, Boehme KL, Wadsworth ME, Staley LA, Alzheimer's Disease Neuroimaging Initiative, Alzheimer's Disease Genetics Consortium, et al. Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2016. doi:10.1016/j.jalz.2015.08.163. PMID: 26449541.
BibTeX
@article{ebbert2016-26449541,
author = {Ebbert, M. T. W. and Boehme, K. L. and Wadsworth, M. E. and Staley, L. A. and {Alzheimer's Disease Neuroimaging Initiative} and {Alzheimer's Disease Genetics Consortium} and Mukherjee, S. and Crane, P. K. and others},
title = {{Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk}},
journal = {Alzheimer's \& dementia : the journal of the Alzheimer's Association},
year = {2016},
doi = {10.1016/j.jalz.2015.08.163},
pmid = {26449541},
url = {https://doi.org/10.1016/j.jalz.2015.08.163}
}
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