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.. DOAJ (DOAJ: Directory of Open Access Journals), 2026-07-01
Topic: Amyloid, tau and blood-test diagnosis
Abstract Mechanisms linking CD33 variants to Alzheimer Disease (AD) are poorly defined. Here, we combine structural, cellular, and genetic analyses to delineate how the CD33M splice isoform, upregulated in carriers of CD33 risk alleles, modulates microglial function. We show that CD33M ectodomain dimerizes, enabling binding of large multi-sialylated molecules. We demonstrate that another AD risk protein - clusterin (CLU) ± Aβ oligomers (but not ApoE) binds with nanomolar avidity to CD33M, but not CD33m. We show that in human monocytes CD33M:CLU binding induces CD33M ITIM phosphorylation, recruits SHP-1, suppresses Aβ phagocytosis, and impairs clearance of amyloid plaques. We identify a soluble CD33M ectodomain fragment (sCD33M) - absent from CD33m-expressing cells - which could contribute to the role of CD33M in AD. Genetic analyses confirm that CD33:CLU interaction modulates amyloid burden, cognition, and disease risk. These findings define a mechanistic CLU:Aβ:CD33M axis, highlighting CD33M dimerization and ligand-binding sites as potential therapeutic targets.
Key findings
- These findings define a mechanistic CLU:Aβ:CD33M axis, highlighting CD33M dimerization and ligand-binding sites as potential therapeutic targets.
Why it matters
This laboratory work describes a mechanistic CLU:Aβ:CD33M axis and identifies CD33M dimerization and ligand-binding sites as potential therapeutic targets. These are structural, cellular, and genetic findings, and no treatment has been tested in patients.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 37/100
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. We have no data on journal's citation record and institution's track record, so those were left out: it earned 34 of the 93 points we could judge it on, which is 37 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (DOAJ (DOAJ: Directory of Open Access Journals)) |
| 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 34 / 93 | Scored on 18 of 20 parts. We have no data for the rest, so they are left out: 34 of the 93 points we could judge it on is 37 out of 100. |
| Total | 37 / 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).
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. DOAJ (DOAJ: Directory of Open Access Journals). 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. DOAJ (DOAJ: Directory of Open Access Journals). 2026. doi:10.1038/s41467-026-75140-3.
BibTeX
@article{dodd2026-c8ae3fc8,
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 = {DOAJ (DOAJ: Directory of Open Access Journals)},
year = {2026},
doi = {10.1038/s41467-026-75140-3},
url = {https://doi.org/10.1038/s41467-026-75140-3}
}