CD33 and clusterin interact biophysically and genetically to modulate Alzheimer risk

2026-07-17

Mechanisms linking CD33 variants to Alzheimer Disease (AD) are poorly defined. Here, we combine structural, cellular, and genetic analyses to delineate how the CD33 M splice isoform, upregulated in carriers of CD33 risk alleles, modulates microglial function. We show that CD33 M 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 CD33 M , but not CD33 m . We show that in human monocytes CD33 M :CLU binding induces CD33 M ITIM phosphorylation, recruits SHP-1, suppresses Aβ phagocytosis, and impairs clearance of amyloid plaques. We identify a soluble CD33 M ectodomain fragment (sCD33 M ) - absent from CD33 m -expressing cells - which could contribute to the role of CD33 M in AD. Genetic analyses confirm that CD33:CLU interaction modulates amyloid burden, cognition, and disease risk. These findings define a mechanistic CLU:Aβ:CD33 M axis, highlighting CD33 M dimerization and ligand-binding sites as potential therapeutic targets.

Full text

DOI https://doi.org/10.1038/s41467-026-75140-3