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Cited by 5Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

A systems immunology analysis of Alzheimer's disease reveals an age‐ and environmental exposure‐independent disturbance in B cell maturation

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Humblet‐Baron, Stephanie, Feng, Yang, Veiga, Rafael, Neumann, Julika, Prezzemolo, Teresa, Pasciuto, Emanuela, Vandenberghe, Rik, Yshii, Lidia +1 more·2025·Alzheimer's & Dementia
DOI 10.1002/alz.70952PMC PMC12645157
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Abstract

INTRODUCTION: Alzheimer's disease is a severe neurodegenerative disorder, with multifactorial mechanisms of disease development and progression. Evidence from genetic association studies, animal models, and clinical investigation suggests a neuroimmunological component to disease, with links to the peripheral immune system. METHODS: Here we applied a systems immunology approach to determine the immunological correlates of Alzheimer's disease. Using high‐dimensional flow cytometry and machine learning, we comprehensively assessed the cellular component of the peripheral immune system in a well‐characterized cohort of 184 Alzheimer's patients and 105 healthy spouses. RESULTS: Using this approach, Alzheimer's patients demonstrated a disturbance in B cell maturation, a feature that was associated not only with disease status but also with cognitive decline. This effect was age and environmental exposure independent, suggesting a disease‐intrinsic relationship between Alzheimer's disease and B cell maturation. DISCUSSION: These results provide an underexplored avenue for improving both mechanistic understanding and therapeutic design in Alzheimer's disease. Highlights: A systems immunology analysis on a cohort of 184 patients with Alzheimer's disease (AD) and 105 healthy spouses. AD demonstrated a defect in B cell maturation, associated with more cognitive decline. The B cell maturation association was age and environmental exposure independent. Additional peripheral immunological changes were associated with AD.

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  • Previous findings showed a decrease in naïve IgD+ CD27 B cells in AD patients.

    “These results confirm previous findings showing a decrease in naïve IgD + CD27 B cells in AD patients while refining the specific subpopulation of naïve B cells implicated”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [93]

    The Background and Discussion report earlier findings of lower naïve B cells in AD patients, and the Results identify a more specific deficit in transitional B cells. Our copy does not establish a decrease in the specifically described IgD+ CD27 B-cell population. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The disturbance in B cell development in AD was not influenced by age or environmental exposures.

    “this disturbance in B cell development was not influenced by age or environmental exposures”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [93]

    The Results section reports that the AD-associated B-cell maturation changes persisted across the studied age range and were not explained by the environmental exposures examined. But the Discussion’s “Strengths and limitations” section says only EBV and CMV were directly tested, and untested exposures cannot be excluded as causes. The unqualified claim that environmental exposures did not influence the disturbance overstates that conclusion. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • AD is associated with a significant and disease-specific disruption of B cell homeostasis.

    “Altogether these data indicate that AD is associated with a significant and disease-specific disruption of B cell homeostasis.”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [93]

    The Results section ('Alzheimer's disease patients exhibit defective maturation within the B cell compartment'; page unavailable) reports reduced immature and transitional B-cell populations in AD patients, supporting a disruption of B-cell homeostasis. The Methods section ('Study design and patient characteristics'; page unavailable) identifies healthy spouse controls, not other disease groups, so the paper does not establish that the disruption is disease-specific. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • A multimodal analysis comparing PBMCs from AD patients and healthy controls identified reduced naïve B cells, particularly immature transitional B cells (CD10 high, CD21 low, CD24 high, CD38 high), as the main driver of the distinct peripheral immune signature of AD.

    “A more recent multimodal analysis using machine learning and statistical models comparing PBMCs from AD patients and healthy controls identified reduced naïve B cells, particularly immature transitional B cells (CD10 high , CD21 low , CD24 high , CD38 high ), as main driver of the distinct peripheral immune signature of AD [93].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [93]

  • B cell production and/or maturation are affected by AD.

    “suggest that B cell production and/or maturation are affected by AD [78,93].”

    From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [93]

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Authors
Humblet‐Baron, S., Feng, Y., Veiga, R., Neumann, J., Prezzemolo, T., Pasciuto, E., Vandenberghe, R., Yshii, L., & Liston, A.
Affiliations
  • Department of Microbiology KU Leuven Immunology and Transplantation Leuven Belgium
  • KU Leuven (BE)
  • University of Cambridge (GB)
  • University of Antwerp (BE)
  • Universitair Ziekenhuis Leuven (BE)
Corresponding author
  • Vandenberghe, Rik
  • Yshii, Lidia
  • Liston, Adrian
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2025-11
Volume
21
Issue
11
Pages
e70952-e70952
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.70952
PMC
PMC12645157
OpenAlex
W4416619491
Cited by
5
References
3
Citations by year
2026: 5
FWCI
1.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Lirias (KU Leuven) (submittedVersion, cc-by-nc-nd)
  • Lirias (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion)
Funders
  • Agentschap Innoveren en Ondernemen (PRISMA)
  • H2020 Societal Challenges (874707)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, B cell maturation
MeSH terms
Machine Learning, Immunoinformatics, Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, B-Lymphocytes, Environmental Exposure, Female, Flow Cytometry, Humans, Male, Middle Aged, Cohort Studies, Cognitive Dysfunction

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