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Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus

Nature Reviews Neurology volume 17, pages 689–701 (2021)Cite this article

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A Publisher Correction to this article was published on 08 October 2021

This article has been updated

Abstract

Dysregulation of the immune system is a cardinal feature of Alzheimer disease (AD), and a considerable body of evidence indicates pathological alterations in central and peripheral immune responses that change over time. Considering AD as a systemic immune process raises important questions about how communication between the peripheral and central compartments occurs and whether this crosstalk represents a therapeutic target. We established a whitepaper workgroup to delineate the current status of the field and to outline a research prospectus for advancing our understanding of peripheral–central immune crosstalk in AD. To guide the prospectus, we begin with an overview of seminal clinical observations that suggest a role for peripheral immune dysregulation and peripheral–central immune communication in AD, followed by formative animal data that provide insights into possible mechanisms for these clinical findings. We then present a roadmap that defines important next steps needed to overcome conceptual and methodological challenges, opportunities for future interdisciplinary research, and suggestions for translating promising mechanistic studies into therapeutic interventions.

Key points

  • Alzheimer disease (AD) should be viewed as a systemic disease that involves dynamic processes in the peripheral and central immune compartments.

  • Clinical studies suggest that the peripheral and central immune systems are dysregulated in AD, are related to cognitive function and clinical status, and may change in a non-linear manner over time; burgeoning evidence also suggests that the roles of innate and adaptive immune processes differ depending on the pathological stage of AD.

  • Animal studies have provided insights into possible mechanisms for peripheral and central immune communication, including direct pathways that involve peripheral immune cell infiltration into the CNS, as well as indirect pathways that involve systemic inflammation-driven modulation of microglial function.

  • Longitudinal clinical studies to evaluate peripheral and central immune mechanisms are needed in combination with comprehensive assessment of the human exposome in demographically diverse cohorts.

  • Further mechanistic studies in animal models are critical to providing a better understanding of peripheral immune cell trafficking to the CNS, adaptive and innate immune system interfaces and astrocyte–microglia crosstalk.

  • Translational and interdisciplinary studies are needed to reconcile differences in immune pathways across species and to develop strategic immune-based therapies that are tailored to disease state and severity.

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Acknowledgements

This manuscript was facilitated by the Alzheimer’s Association International Society to Advance Alzheimer’s Research and Treatment (ISTAART), through the Immunity and Neurodegeneration Professional Interest Area (PIA). The views and opinions expressed by the authors in this publication represent those of the authors and do not necessarily reflect those of the PIA membership, ISTAART or the Alzheimer’s Association. B.M.B. is a funded investigator of the NIH/NIA (R01 AG058772) and the Department of Defense CDMRP. M.G.T. is a funded investigator of the NIH/NIA (7RF1AG057247), the Parkinson’s Foundation and the Michael J. Fox Foundation for Parkinson’s Research. G.D. is a funded investigator of the Fondation Plan Alzheimer, Fondation pour la Recherche Medicale, LECMA/Fondation Vaincre Alzheimer and Alzheimer Research UK. M.T.H. is a funded investigator of the German Research Council (DFG) Cluster of Excellence and has received support from this work through an NIH grant (R01 AG059752-02).

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Authors and Affiliations

  1. Behavioral Neurology Section, Department of Neurology, University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Brianne M. Bettcher

  2. Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, FL, USA

    Malú G. Tansey

  3. Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, Team “Immune System and Neuroinflammation”, Hôpital Saint-Antoine, Paris, France

    Guillaume Dorothée

  4. Department of Neurodegenerative Diseases & Geropsychiatry/Neurology, University of Bonn Medical Center, Bonn, Germany

    Michael T. Heneka

  5. Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA

    Michael T. Heneka

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  1. Brianne M. Bettcher
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  2. Malú G. Tansey
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  3. Guillaume Dorothée
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  4. Michael T. Heneka
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The authors contributed equally to all aspects of the article.

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Correspondence to Brianne M. Bettcher.

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Competing interests

M.G.T. is a member of the Medical Scientific Advisory Group to the Alzheimer’s Association and a consultant to INmune Bio. G.D. is listed as an inventor on patent WO2014206899A1 related to a peripheral immunomodulatory approach for treating Alzheimer disease and related disorders, and on patent WO2018172540A1 related to peripheral immune biomarkers for predicting the progression of Alzheimer disease. The other authors declare no competing interests.

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Bettcher, B.M., Tansey, M.G., Dorothée, G. et al. Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus. Nat Rev Neurol 17, 689–701 (2021). https://doi.org/10.1038/s41582-021-00549-x

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