Single‐Cell RNA Sequencing of Peripheral Blood Reveals Immune Cell Signatures in Alzheimer’s Disease

Abstract Background Alzheimer’s disease (AD) pathogenesis involves various immune‐related phenomena both in central nervous system and peripheral blood. However, the characteristics of peripheral immune cells is poorly defined in AD at a single cell level. Method We profile 36,849 peripheral blood mononuclear cells (PBMC) from AD patients with amyloid positive (Aβ+) and normal controls with amyloid negative (Aβ‐) by 5' single‐cell transcriptome and immune repertoire sequencing with cell ranger standard analysis procedure. Based on the gene expression profile, immune cells were clustered and visualized by t‐distributed stochastic neighbour embedding (tSNE). In addition, we described the features of T cell receptor (TCR) and B cell receptor (BCR) repertoire from clonotypes, V gene and J gene skewed usage, amino acid length, and diversity of complementarity determining region 3 (CDR3). Result We revealed five immune cell subsets, CD4+ T cells, CD8+ T cells, B cells, natural killer cells, and monocytes‐macrophages cells, disentangled the characteristic alterations of cell subset proportion and gene expression patterns in AD. A total of 31 cell‐type‐specific key genes, comprising abundant human leucocyte antigen genes, and multiple immune related pathways were identified by protein‐protein interaction network and pathway enrichment analysis. We also found High‐frequency amplification clonotypes in T cells and B cells and the decreased diversity in T cells were detected in AD. Conclusion We found abnormal immune infiltration and complex TCR and BCR alterations were presented in AD peripheral blood. As clone amplification suggested the activation of adaptive immune response against specific antigens, we speculated peripheral adaptive immune response, especially mediated by T cell, may have a role in the pathogenesis of AD. This finding may also contribute to further research regarding disease mechanism and development of immune related biomarkers or therapy.