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CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk
Roger B. Dodd, Masahiro Enomoto, Ye Zhou, Kanayo Satoh, Yalun Zhang, Fusheng Chen, Beatrice Acheson, Deniz Ghaffari et al.. Nature Communications, 2026-07-17
Topic: Amyloid, tau and blood-test diagnosis
ABSTRACT We report the results of structural, functional and genetic studies on the CD33 sialic acid- binding receptor that reveal how non-coding variants in CD33 alter risk for Alzheimer’s disease (AD). The full-length CD33 M isoform, whose expression is upregulated by non-coding AD-risk alleles, preferentially forms dimers at the cell surface, where they interact with AD-related proteins (clusterin and Aβ). This interaction induces CD33 M inhibitory signalling and downregulates protective microglial functions including phagocytic removal of amyloid plaques. Human brain expression quantitative trait loci (eQTL) and causal mediation analyses confirm that quantitative interactions between CLU and CD33 genotypes modulate AD phenotypes and suggest that genotypes at these loci might be used to personalise future therapeutic approaches. Our work also highlights several other unexpected aspects of CD33 biology, including a soluble shed extracellular fragment of CD33 M and a similar soluble secreted product arising from a truncating mutation in the CD33 extracellular domain (CD33 MΔ4bp ).
Key findings
- ABSTRACT We report the results of structural, functional and genetic studies on the CD33 sialic acid- binding receptor that reveal how non-coding variants in CD33 alter risk for Alzheimer’s disease (AD).
- Human brain expression quantitative trait loci (eQTL) and causal mediation analyses confirm that quantitative interactions between CLU and CD33 genotypes modulate AD phenotypes and suggest that genotypes at these loci might be used to personalise future therapeutic approaches.
Why it matters
This study reports that non-coding CD33 variants alter Alzheimer's risk by affecting the CD33 M isoform, which forms dimers that interact with clusterin and Aβ and downregulate protective microglial functions such as plaque removal. The authors suggest that genotypes at CD33 and CLU loci might be used to personalize future therapeutic approaches, but no treatment was tested in this work.
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Study details
- Evidence strengthLow
How this study scored 40/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record and institution's track record, so those were left out: it earned 37 of the 93 points we could judge it on, which is 40 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature Communications) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 5 / 5 | 2026 — within 1 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 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 1 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.5 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 3 / 6 | Cited 4.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 1 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Peter St George‐Hyslop: h-index 121 (OpenAlex, whole career) |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 0 institution(s) in 0 countries — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40766450) |
| Free to read | 2 / 2 | Free to read |
| Points | 37 / 93 | Scored on 18 of 20 parts. We have no data for the rest, so they are left out: 37 of the 93 points we could judge it on is 40 out of 100. |
| Total | 40 / 100 | — |
What each of these 20 components measures, and what this score is not →
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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
Dodd, R. B., Enomoto, M., Zhou, Y., Satoh, K., Zhang, Y., Chen, F., et al. (2026). CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk. Nature Communications. https://doi.org/10.1038/s41467-026-75140-3
Vancouver
Dodd RB, Enomoto M, Zhou Y, Satoh K, Zhang Y, Chen F, et al. CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk. Nature Communications. 2026. doi:10.1038/s41467-026-75140-3. PMID: 40766450.
BibTeX
@article{dodd2026-40766450,
author = {Dodd, Roger B. and Enomoto, Masahiro and Zhou, Ye and Satoh, Kanayo and Zhang, Yalun and Chen, Fusheng and Acheson, Beatrice and Ghaffari, Deniz and others},
title = {{CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk}},
journal = {Nature Communications},
year = {2026},
doi = {10.1038/s41467-026-75140-3},
pmid = {40766450},
url = {https://doi.org/10.1038/s41467-026-75140-3}
}