CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk
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 ).
Authors
- Sandeep Satapathy (ORCID: https://orcid.org/0000-0003-1479-1280)
- Eduard Sergienko (ORCID: https://orcid.org/0009-0003-2595-2227)
- Zena K. Chatila (ORCID: https://orcid.org/0000-0002-4383-6305)
- Zvi Fishelson (ORCID: https://orcid.org/0000-0001-7097-6357)
- Xunde Xian (ORCID: https://orcid.org/0000-0003-3059-1254)
- Mitsuhiko Ikura (ORCID: https://orcid.org/0000-0002-9524-1303)
- Kirstin A. Tamucci (ORCID: https://orcid.org/0000-0002-7033-807X)
- Ronak Patel (ORCID: https://orcid.org/0000-0002-8871-6390)
- William Meadows
- Jean Sévalle
- Jennifer West (ORCID: https://orcid.org/0000-0001-8708-921X)
- Elizabeth M. Bradshaw (ORCID: https://orcid.org/0000-0002-6766-4325)
- Joachim Herz (ORCID: https://orcid.org/0000-0002-8506-3400)
- Mark R. Wilson (ORCID: https://orcid.org/0000-0002-9551-7445)
- Wesley B. Asher (ORCID: https://orcid.org/0000-0001-7437-218X)
- Philip L. De Jager (ORCID: https://orcid.org/0000-0002-8057-2505)
- Andrey A. Bobkov (ORCID: https://orcid.org/0000-0002-9028-3635)
- Dan Frenkel (ORCID: https://orcid.org/0000-0002-7494-6857)
- Kanayo Satoh (ORCID: https://orcid.org/0009-0000-4520-2560)
- Christopher Böhm
- Christopher M. Johnson (ORCID: https://orcid.org/0000-0002-1244-5926)
- Seema Qamar (ORCID: https://orcid.org/0000-0003-1189-206X)
- Peter St George‐Hyslop (ORCID: https://orcid.org/0000-0003-0796-7209)
- Suzanne J. Randle
- Jennifer L. Hall (ORCID: https://orcid.org/0000-0002-5103-5399)
- Yalun Zhang (ORCID: https://orcid.org/0000-0002-4078-4087)
- Jonathan A. Javitch (ORCID: https://orcid.org/0000-0001-7395-2967)
- Annie Lee (ORCID: https://orcid.org/0000-0003-3726-6024)
- Masahiro Enomoto (ORCID: https://orcid.org/0000-0002-9411-2999)
- Alondra Schweizer Burguete (ORCID: https://orcid.org/0000-0003-0324-3334)
- Jennifer K. Griffin (ORCID: https://orcid.org/0000-0001-8390-7502)
- Sirkku Pollari
- Badri Narayan Vardarajan (ORCID: https://orcid.org/0000-0002-5560-4085)
- Roger B. Dodd (ORCID: https://orcid.org/0000-0003-4268-1863)
- Deniz Ghaffari
- Fusheng Chen (ORCID: https://orcid.org/0000-0001-8525-4154)
- Mamunur Rashid (ORCID: https://orcid.org/0000-0001-6768-1814)
- Minghua Liu (ORCID: https://orcid.org/0000-0001-6147-0565)
- Ye Zhou (ORCID: https://orcid.org/0000-0003-3861-3120)
- David A. Bennett
- Mason J. Kralovec
- Paul Fraser
- Beatrice Acheson
- George V. Dukas
- Cory D. Rillahan
- Elizabeth Sayn-Wittgenstein
Institutions
- Rush University Medical Center (US)
- University Health Network (CA)
- Tel Aviv University (IL)
- MRC Laboratory of Molecular Biology (GB)
- University of Toronto (CA)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- University of Wollongong (AU)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- Discovery Institute (US)
- Columbia University Irving Medical Center (US)
- German Center for Neurodegenerative Diseases (DE)
- Princess Margaret Cancer Centre (CA)
- New York Psychoanalytic Society and Institute (US)
- National Institute for Health and Care Research (GB)
- Ted Rogers Centre for Heart Research (CA)
- Occupational Cancer Research Centre (CA)
- Dana-Farber Cancer Institute (US)
- Institute on Aging (US)
- New York State Psychiatric Institute
- Columbia University (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-07-17
- DOI
- https://doi.org/10.1038/s41467-026-75140-3
- Citations
- 3
- Primary Topic
- Clusterin in disease pathology
- Type
- article
- Field-Weighted Citation Impact
- 5.76
Funders
- Alzheimer's Association
- Wellcome
- BrightFocus Foundation
- Hope for Depression Research Foundation
- St. Jude Children's Research Hospital
- Wellcome Trust
- Diamond Light Source
- University of Oxford
- Tel Aviv University
- National Institutes of Health
- Canadian Institutes of Health Research
- Medical Research Council