The DOI matches its Crossref record; 31 of the 32 references it cites were found in a registry or an index.
Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease
Open accessAbstract
Alzheimer's disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function 1. However, little is known about the contribution of the adaptive immune response in Alzheimer's disease 2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer's disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer's disease that consists of increased numbers of CD8+ T effector memory CD45RA+ (T EMRA) cells. In a second cohort, we found that CD8+ T EMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8+ T EMRA cells in the cerebrospinal fluid of patients with Alzheimer's disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer's disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer's disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“T-lymphocyte infiltration into the brain has been previously reported in AD patients and has been associated with impaired cognition (Gate et al., 2020; Jorfi et al., 2023).”
From Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy (2024) · cites this paper as Gate et al., 2020
Experimental — accuracy not yet measuredIn the citing paper
“Dysfunctional meninges also represent an important contributor to neuroinflammation in neurodegenerative diseases by acting as a checkpoint for T-cell infiltration.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [686]
In the citing paper
“Finally, the systemic chronic inflammation resulting from immunosenescence and non-neurotropic viral infection compels immune cells in the peripheral blood to penetrate the blood-brain barrier (BBB) and choroid plexus and enter the brain,345,346 Additionally, immune cells originating from the cranial bone marrow migrate to the meninges,347 thereby promoting neuroinflammation and neuronal”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [348]
In the citing paper
“Indeed, increased clonal expansion and CD8+ T cell infiltration in the brain are observed both in AD patients and during aging (48, 49).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [48]
In the citing paper
“Interestingly, several recent studies suggest that AD is associated with viral infection (47, 48).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [48]
In the citing paper
“The infiltration of clonally expanded T cells and B cells is also observed in the brain and other tissues with ageing in mice and humans69,71–73, and it is accentuated in age-related diseases74,75.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [74]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment
Nasreddine, Z. S., Phillips, N. A., Bédirian, V., Charbonneau, S., Whitehead, V., Collin, I., Cummings, J. L., & Chertkow, H. (2005) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2005.53221.x · Cited by 25,553
Comprehensive Integration of Single-Cell Data
Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W. M., Hao, Y., Stoeckius, M., Smibert, P., & Satija, R. (2019) · Cell · doi:10.1016/j.cell.2019.05.031 · Cited by 15,453
Integrating single-cell transcriptomic data across different conditions, technologies, and species
Butler, A., Hoffman, P., Smibert, P., Papalexi, E., & Satija, R. (2018) · Nature Biotechnology · doi:10.1038/nbt.4096 · Cited by 13,174
Two subsets of memory T lymphocytes with distinct homing potentials and effector functions
Sallusto, F., Lenig, D., Förster, R., Lipp, M., & Lanzavecchia, A. (1999) · Nature · doi:10.1038/44385 · Cited by 5,846
Structural and functional features of central nervous system lymphatic vessels
Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D., Rouhani, S. J., Peske, J. D., Derecki, N. C., Castle, D., Mandell, J. W., Lee, K. S., et al. (2015) · Nature · doi:10.1038/nature14432 · Cited by 4,413
Central Memory and Effector Memory T Cell Subsets: Function, Generation, and Maintenance
Sallusto, F., Geginat, J., & Lanzavecchia, A. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104702 · Cited by 3,067
How neuroinflammation contributes to neurodegeneration
Ransohoff, R. M. (2016) · Science · doi:10.1126/science.aag2590 · Cited by 1,967
Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh019 · Cited by 1,575
Identifying specificity groups in the T cell receptor repertoire
Glanville, J., Huang, H., Nau, A., Hatton, O., Wagar, L. E., Rubelt, F., Ji, X., Han, A., Krams, S. M., Pettus, C., et al. (2017) · Nature · doi:10.1038/nature22976 · Cited by 1,026
Self-citationT cells from patients with Parkinson’s disease recognize α-synuclein peptides
Sulzer, D., Alcalay, R. N., Garretti, F., Cote, L., Kanter, E., Agin-Liebes, J., Liong, C., McMurtrey, C., Hildebrand, W. H., Mao, X., et al. (2017) · Nature · doi:10.1038/nature22815 · Cited by 866
Cited by
Sorted by citations
Items 1,001–1,002 of 1,002
Active Vaccination Strategies for Alzheimer's Disease: An Expanded Review
Comitato, A., Neri, A., & Cossarizza, A. (2026) · European Journal of Immunology · doi:10.1002/eji.70250
Limbrick, O. W., Vohra, H. Z., Swarup, R., Dhingra, S., Michenkova, M., Crouthamel, J., Boysen, C., Shumilov, K., Strahle, J. M., McAllister, J. P., II, et al. (2026) · Scientific Reports · doi:10.1038/s41598-026-64058-x
Metadata
- Authors
- 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., McBride, A., Pluvinage, J., Elahi, F., Tam, G. K.-Y., Kim, Y., Greicius, M., Wagner, A. D., Aigner, L., Galasko, D. R., Davis, M. M., & Wyss-Coray, T.
- Affiliations
- VA Palo Alto Health Care System (US)
- Stanford Medicine (US)
- Stanford University (US)
- Paracelsus Medical University (AT)
- Utrecht University (NL)
- University of California, San Francisco (US)
- University of California San Diego (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Gate, David
- ORCID
- Venue
- Nature
- Published
- 2020-01-08
- Volume
- 577
- Issue
- 7790
- Pages
- 399-404
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7445078
- OpenAlex
- W3000319248
- Cited by
- 992
- References
- 32
- Citations by year
- 2026: 158 · 2025: 161 · 2024: 160 · 2023: 166 · 2022: 149 · 2021: 129 · 2020: 66
- FWCI
- 50.05
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Veterans Affairs
- Cure Alzheimer's Fund
- Multiple Sclerosis Society
- NOMIS Stiftung
- National Institutes of Health (AI057229)
- National Institute on Aging (F32AG055255, AG055255-01A1, P50AG047366, AG045034, R01 AG045034 05, R01AG045034, R01AG048076, K24AG045333, P01AG019724, P30AG062422, P30AG066515, T32AG023481)
- National Institute of Allergy and Infectious Diseases (U19AI057229)
- National Institute of Neurological Disorders and Stroke (R00NS112458, K99NS112458)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- Alzheimer's disease, CD8+ T cells, TEMRA cells, cerebrospinal fluid, T cell clonal expansion, T cell receptor repertoire, adaptive immune response, neuroinflammation, age-related neurodegeneration, cognitive decline
- MeSH terms
- Aged, Alzheimer Disease, Amino Acid Sequence, Cerebrospinal Fluid, Humans, Immunologic Memory, Middle Aged, Receptors, Antigen, T-Cell, Cohort Studies, CD8-Positive T-Lymphocytes, Sequence Analysis, Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
