Single-Cell Transcriptome-Wide Mendelian Randomization and Colocalization Analysis Reveals Immune Cell-Specific Mechanisms in Alzheimer's Disease

Genetically predicted TNF expression in CD4+SOX4+ T cells is strongly linked to Alzheimer’s disease risk, with Bayesian colocalization PP.H4 = 0.833.

• Why it matters: Immune-cell genetic regulation of Alzheimer’s disease is poorly resolved at the cell-type level, limiting identification of causal genes and mechanisms in peripheral immunity.
• What they did: Using cis-eQTLs from 14 peripheral blood immune cell types in OneK1K as exposures and AD GWAS GCST90565439 as outcome, two-sample MR plus Bayesian colocalization and 1M-scBloodNL replication were performed.
• The result: MR found 187 significant gene–cell type associations (161 candidate causal genes), with 141 genes specific to one immune cell type; TNF colocalization implies a shared signal and PheWAS concentrated immune/hematology traits.

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