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  • Systematic Review
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Peripheral immune function and Alzheimer’s disease: a living systematic review and critical appraisal

Molecular Psychiatry (2023)Cite this article

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Abstract

Background

A growing body of literature examines the relationship between peripheral immune function and Alzheimer’s Disease (AD) in human populations. Our living systematic review summarizes the characteristics and findings of these studies, appraises their quality, and formulates recommendations for future research.

Methods

We searched the electronic databases PubMed, PsycINFO, and Web of Science, and reviewed references of previous reviews and meta-analyses to identify human studies examining the relationship between any peripheral immune biomarkers and AD up to September 7th, 2023. We examined patterns of reported statistical associations (positive, negative, and null) between each biomarker and AD across studies. Evidence for each biomarker was categorized into four groups based on the proportion of studies reporting different associations: corroborating a positive association with AD, a negative association, a null association, and presenting contradictory findings. A modified Newcastle–Ottawa scale (NOS) was employed to assess the quality of the included studies.

Findings

In total, 286 studies were included in this review. The majority were cross-sectional (n = 245, 85.7%) and hospital-based (n = 248, 86.7%), examining relationships between 187 different peripheral immune biomarkers and AD. Cytokines were the most frequently studied group of peripheral immune biomarkers. Evidence supported a positive association with AD for six biomarkers, including IL-6, IL-1β, IFN-γ, ACT, IL-18, and IL-12, and a negative association for two biomarkers, including lymphocytes and IL-6R. Only a small proportion of included studies (n = 22, 7.7%) were deemed to be of high quality based on quality assessment.

Interpretation

Existing research on peripheral immune function and AD exhibits substantial methodological variations and limitations, with a notable lack of longitudinal, population-based studies investigating a broad range of biomarkers with prospective AD outcomes. The extent and manner in which peripheral immune function can contribute to AD pathophysiology remain open questions. Given the biomarkers that we identified to be associated with AD, we posit that targeting peripheral immune dysregulation may present a promising intervention point to reduce the burden of AD.

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Fig. 1: Theoretical mechanistic framework depicting the hypothesized relationship between peripheral and central immune dysregulation and neurophysiology.
Fig. 2
Fig. 3: Summary of reported findings across included studies.
Fig. 4: Quality assessment of included studies on peripheral immunity and AD.

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Data availability

The data used in this study are all presented in the main tables or supplementary materials.Additional data and code to generate findings reported in this study are available from theGitHub repository (https://github.com/Peripheral-immune-AD/Peripheral-immune-and-AD).

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Acknowledgements

CL was supported by NIA R01AG070953 and R01AG075719; GAN was supported by NIA R00AG062749 and R01AG075719; RCS and was supported by NIA R01AG075719; AEA was supported by NIA R01AG075719.

Author information

Author notes

  1. These authors contributed equally: Chihua Li, Rebecca C. Stebbins, Grace A. Noppert.

Authors and Affiliations

  1. Social Environment and Health Program, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA

    Chihua Li & Grace A. Noppert

  2. Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA

    Chihua Li

  3. Department of Epidemiology, School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Chihua Li

  4. Robert N. Butler Columbia Aging Center, Mailman School of Public Health, Columbia University, New York City, NY, USA

    Rebecca C. Stebbins & Allison E. Aiello

  5. Department of Epidemiology, Milken Institute School of Public Health, The George Washington University, Washington, DC, USA

    Constanza X. Carney

  6. Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Chunyu Liu

  7. Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China

    Chunyu Liu

  8. Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Ashley R. M. Sapp

  9. Department of Anthropology, Northwestern University, Evanston, IL, USA

    Elijah J. Watson

  10. Department of Epidemiology, Mailman School of Public, Columbia University, New York City, NY, USA

    Allison E. Aiello

Authors
  1. Chihua Li
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  2. Rebecca C. Stebbins
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  3. Grace A. Noppert
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  4. Constanza X. Carney
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  5. Chunyu Liu
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  6. Ashley R. M. Sapp
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  7. Elijah J. Watson
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  8. Allison E. Aiello
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Contributions

RCS, GAN, and AEA initiated the study. CL and CL were responsible for study design, data collection, analysis, and visualization. CL, RCS, GAN, and AEA interpreted the study findings. CL, RCS, and GAN wrote the first draft of the manuscript. AEA revised the manuscript. All authors have read, revised, and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Chihua Li.

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Li, C., Stebbins, R.C., Noppert, G.A. et al. Peripheral immune function and Alzheimer’s disease: a living systematic review and critical appraisal. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02355-x

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  • DOI: https://doi.org/10.1038/s41380-023-02355-x

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