Multi-omic characterization of CR1+ oligodendrocytes reveals conserved pathology and a peripheral biomarker in Alzheimer’s disease

Complement receptor 1 ( CR1 ) is among the most consistently identified genetic risk factors for late-onset Alzheimer’s disease (AD), yet the cell type through which this genetic risk operates remains unclear. Recent single-nucleus RNA sequencing (snRNA-seq) studies have linked AD risk variants to CR1 expression specifically in oligodendrocytes (ODC). However, the functional consequences, cross-regional consistency, and biomarker potential of CR1 upregulation in ODC remain largely unexplored. AD GWAS colocalization, Mendelian randomization (MR), and snATAC-seq were used to link the CR1 locus to ODC. Three independent snRNA-seq cohorts spanning the prefrontal cortex (PFC) and middle temporal gyrus (MTG) were integrated for differential expression, functional enrichment, pseudotime, and cell–cell communication analyses of CR1 + and CR1 − ODC. Peripheral blood CR1 transcript levels were assessed in the ADNI cohort ( n = 442) and plasma soluble CR1 (sCR1) protein was measured by ELISA in an independent in-house cohort ( n = 108). GWAS colocalization and MR established that AD genetic risk at the CR1 locus acts through increased ODC CR1 expression. Across three independent brain cohorts, CR1 was selectively elevated in AD ODC, with CR1 + subclusters exhibiting microtubule destabilization, vesicle impairment, and loss of synaptic–myelin support; among differentially expressed genes, HAPLN2 was the sole gene consistently downregulated across all cohorts. In peripheral blood, elevated CR1 transcript levels correlated with cognitive decline, independent of APOE4 and ATN biomarkers, and the combination of CR1 and APOE4 improved diagnostic classification (AUC = 0.789). Plasma sCR1 protein was further measured by ELISA, with elevated levels in AD and strong discriminative performance (AUC = 0.935). CR1 marks a cross-regionally conserved population of functionally impaired ODC in AD, genetically associated with AD risk at the CR1 locus, characterized by HAPLN2 downregulation and synaptic-myelin disconnection. Peripheral CR1 may serve as a candidate biomarker reflecting this ODC pathology, independently of classical AD biomarker pathways, warranting further validation.