Single-Cell RNA Sequencing of Peripheral Blood Reveals Immune Cell Signatures in Alzheimer’s Disease
Open accessAbstract
The peripheral immune system is thought to affect the pathology of the central nervous system in Alzheimer’s disease (AD). However, current knowledge is inadequate for understanding the characteristics of peripheral immune cells in AD. This study aimed to explore the molecular basis of peripheral immune cells and the features of adaptive immune repertoire at a single cell level. We profiled 36,849 peripheral blood mononuclear cells from AD patients with amyloid-positive status and normal controls with amyloid-negative status by 5’ single-cell transcriptome and immune repertoire sequencing using the cell ranger standard analysis procedure. We revealed five immune cell subsets: CD4+ T cells, CD8+ T cells, B cells, natural killer cells, and monocytes–macrophages cells, and disentangled the characteristic alterations of cell subset proportion and gene expression patterns in AD. Thirty-one cell type-specific key genes, comprising abundant human leukocyte 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 and B cells and decreased diversity in T cells in AD. As clone amplification suggested the activation of an adaptive immune response against specific antigens, we speculated that the peripheral adaptive immune response, especially mediated by T cells, may have a role in the pathogenesis of AD. This finding may also contribute to further research regarding disease mechanism and the development of immune-related biomarkers or therapy.
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Single cell BCR sequencing identified the amplification of high-frequency B cell clonotypes in AD samples.
“single cell BCR sequencing identified the amplification of highfrequency B cell clonotypes in AD samples”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [94]
B cells are activated against specific antigens in AD.
“suggesting B cell activation against specific antigens [94].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [94]
The single cell RNA sequencing and BCR sequencing studies were limited in sample size and did not identify antigens driving B cell clonotype expansion.
“Although both studies were limited in their sample size and did not identify antigens driving B cell clonotype expansion”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [94]
Single cell RNA sequencing of PBMCs of AD patients revealed altered gene expression in B cells.
“Single cell RNA sequencing of PBMCs of AD patients revealed altered gene expression in B cells [84,94].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [94]
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Cites
Complement and microglia mediate early synapse loss in Alzheimer mouse models
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“In the CNS, microglia, the most important immune cells in the nervous microenvironment, can convert to an activated state to phagocytize and remove amyloid beta (Aß), and they promote the release of inflammatory cytokines, thus accelerating neuronal damage (4).”
BackgroundClonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease
Gate, D., Saligrama, N., Leventhal, O., Yang, A. C., Unger, M. S., Middeldorp, J., Chen, K., Lehallier, B., Channappa, D., De Los Santos, M. B., et al. (2020) · Nature · doi:10.1038/s41586-019-1895-7 · Cited by 992 · see citing works
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The decrease of CD8-positive lymphocytes in Alzheimer's disease
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Is there a role for B cells in Alzheimer's disease?
Charavner, E.-L., Fillatreau, S., & El Behi, M. (2026) · Cellular Immunology · doi:10.1016/j.cellimm.2026.105154
- Authors
- Xu, H., & Jia, J.
- Affiliations
- Capital Medical University (CN)
- Ministry of Education of the People's Republic of China (CN)
- Corresponding author
- Jia, Jianping
- ORCID
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2021-08-09
- Volume
- 12
- Pages
- 645666-645666
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC8382575
- OpenAlex
- W3189049907
- Cited by
- 149
- References
- 5
- Citations by year
- 2026: 18 · 2025: 31 · 2024: 49 · 2023: 28 · 2022: 21 · 2021: 1 · 2012: 1
- FWCI
- 11.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (81530036, 31627803, U20A20354)
- National Key Scientific Instrument and Equipment Development Projects of China (81530036, 31627803, U20A20354)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- Alzheimer's disease, peripheral blood mononuclear cells, peripheral immune cells, adaptive immune response, T cell clonotypes, B cell clonotypes, CD4+ T cells, CD8+ T cells, natural killer cells, monocytes/macrophages, amyloid, immune cell deconvolution, immune-related biomarkers
- MeSH terms
- Aged, Alzheimer Disease, Humans, Lymphocytes, Middle Aged, Receptors, Antigen, B-Cell, Receptors, Antigen, T-Cell, Sequence Analysis, RNA, Gene Expression Profiling, Single-Cell Analysis, Protein Interaction Maps
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