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Cited by 27Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Altered T-cell reactivity in the early stages of Alzheimer's disease

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Rickenbach, Chiara, Mallone, Anna, Häusle, Lars, Frei, Larissa, Seiter, Sarina, Sparano, Colin, Kirabali, Tunahan, Blennow, Kaj +8 more·2025·Brain
DOI 10.1093/brain/awaf167PMC PMC12404719
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Abstract

The adaptive immune system and neurodegenerative Alzheimer's disease (AD) are intertwined in multiple ways. Recent studies have reported alterations of the adaptive immune system in early AD stages, such as preclinical AD and mild cognitive impairment (MCI) due to AD. However, the identity of specific antigenic targets and whether the respective response is beneficial or detrimental during disease progression are still open questions. Herein, we describe cross-sectional analyses of blood and CSF from three different study populations covering early AD stages. We employed high-dimensional mass cytometry, single-cell RNA-sequencing, ex vivo T-cell secretome analysis, and antigen presentation assays to achieve a comprehensive characterization of adaptive immune cell populations. Our results show that subjects at the stage of asymptomatic, preclinical AD can mount a CD4+ T helper cell response towards amyloid-β peptide and display an early enrichment of CD8+ T effector memory cells re-expressing CD45RA (TEMRA cells) in CSF, combined with a less immunosuppressive gene signature of peripheral regulatory T cells. Conversely, in MCI we observed increased frequencies of CD8+ TEMRA/effector cells in the periphery characterized by a pro-inflammatory gene expression profile, and generally decreased antigen responsiveness. Our results demonstrate the complexity of adaptive immune changes in early AD and suggest that it may be beneficial to promote specific CD4+ T-cell responses in the preclinical stage, while in MCI it may be important to therapeutically target CD8+ T-cell responses if these prove to be harmful.

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  • CD28-positive microglia should be treated as part of a broader stage-dependent neuroimmune circuit involving microglia, plaques, and adaptive immune cells.

    “These findings strengthen the rationale for treating CD28-positive microglia not as an isolated molecular curiosity, but as part of a broader stage-dependent neuroimmune circuit involving microglia, plaques, and adaptive immune cells [37,39].”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [37]

    The Discussion reports stage-dependent changes in adaptive immune cells in early Alzheimer’s disease, including T-cell responses to amyloid-β, and mentions a possible interaction between CD8+ T cells and microglia. It does not identify CD28-positive microglia or establish a circuit linking them with plaques and adaptive immune cells; that specific extension is the citing authors’ interpretation. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • In mouse models, clonally expanded CD8-positive T cells interact dynamically with microglia: early CD8-positive T-cell activity can worsen amyloid pathology and constrain DAM-like microglial transition, whereas later T-cell states may become more tissue-resident or regulatory.

    “In mouse models, clonally expanded CD8-positive T cells have also been shown to interact dynamically with microglia: early CD8-positive T-cell activity can worsen amyloid pathology and constrain DAM-like microglial transition, whereas later T-cell states may become more tissue-resident or regulatory.”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [37]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

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  • CD4-positive T cells in preclinical Alzheimer's disease show a type 2 helper profile and reactivity against Aβ-derived peptides, whereas MCI subjects show increased pro-inflammatory CD8-positive effector/TEMRA cells.

    “Recent human work combining CyTOF, single-cell RNA sequencing, T-cell secretome analysis, and antigen-presentation assays reported that CD4-positive T cells in preclinical Alzheimer’s disease show a type 2 helper profile and reactivity against Aβ-derived peptides, whereas MCI subjects show increased pro-inflammatory CD8-positive effector/TEMRA cells.”

    From Lymphoid-like Suppressive Microglia in Alzheimer’s Disease: A New Neuroimmune Regulatory Axis? (2026) · cites this paper as [37]

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Authors
Rickenbach, C., Mallone, A., Häusle, L., Frei, L., Seiter, S., Sparano, C., Kirabali, T., Blennow, K., Zetterberg, H., Ferretti, M. T., Kulic, L., Hock, C., Nitsch, R. M., Treyer, V., Gietl, A., & Gericke, C.
Affiliations
  • University of Zurich (CH)
  • ETH Zurich (CH)
  • University of Science and Technology of China (CN)
  • University of Wisconsin–Madison (US)
  • Karolinska Institutet (SE)
  • F. Hoffmann-La Roche AG (CH)
  • Institute for Regenerative Medicine—IREM, University of Zurich , 8952 Schlieren ,
Corresponding author
Gericke, Christoph
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2025-05-05
Volume
148
Issue
9
Pages
3364-3378
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awaf167
PMC
PMC12404719
OpenAlex
W4410105792
Cited by
27
References
82
Citations by year
2026: 24 · 2025: 3
FWCI
17.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc)
Funders
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF 320030‐125387/1, 125387, 124111, 320030)
  • Hjärnfonden (ALZ2022-0006), FO2017‑0243)
  • Vetenskapsrådet (2017-00915, 2022-01018, 2022-00732, 2023-00356, 2019-02397)
  • Universität Zürich
  • Mäxi-Stiftung
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, preclinical Alzheimer's disease, mild cognitive impairment, T cell response, CD4+ T helper cells, amyloid-beta, CD8+ T cells, TEMRA cells, regulatory T cells, cerebrospinal fluid, blood, adaptive immune response, antigen presentation, neuroinflammation, immunosuppression
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, T-Lymphocytes, CD4-Positive T-Lymphocytes, Amyloid beta-Peptides, CD8-Positive T-Lymphocytes, Cognitive Dysfunction

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