Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus
Open accessAbstract
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.
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Oxidative stress induced by inflammation and toxicity driven by cytokines may further the decay of the nigrostriatal pathway, thereby hastening the progression of idiopathic PD.
“Oxidative stress induced by inflammation and toxicity driven by cytokines may further the decay of the nigrostriatal pathway, thereby hastening the progression of idiopathic PD. 37”
From Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications (2024) · cites this paper as [37]
The State of the field section (Mechanistic insight from animal studies; page unavailable) describes cytokine-related neuronal damage and inflammation contributing to neurodegeneration in Alzheimer disease. It does not establish inflammation-induced oxidative stress, nigrostriatal pathway decay, or faster progression of idiopathic Parkinson disease; its brief mention of Parkinson disease concerns an open question about T-cell infiltration. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThis phenomenon (cytokine increase, NF-κB activation, oxidative damage) has been noted in the cerebrospinal fluid and brain tissue of living PD patients and in postmortem brain autopsies of those with PD.
“This phenomenon has been noted in the cerebrospinal fluid and brain tissue of living PD patients and in postmortem brain autopsies of those with PD. 37”
From Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications (2024) · cites this paper as [37]
The “Clinical studies of immune dysregulation” section reports elevated CSF pro-inflammatory markers in Alzheimer disease, not Parkinson disease. The passages do not support the claim about NF-κB activation, oxidative damage, brain tissue, or postmortem findings in PD patients; no page number is available in our copy. (LLM, conf=0.78)
Experimental — accuracy not yet measuredCD4+ and CD8+ T cells have been most extensively studied, with evidence of their presence in brain parenchyma and CSF of AD patients, where they modulate neuroinflammation and contribute to neurodegeneration.
“Among these, CD4 + and CD8 + T cells have been the most extensively studied, with compelling evidence of their presence in the brain parenchyma and cerebrospinal fluid (CSF) of AD patients, where they have been shown to modulate neuroinflammation and contribute to neurodegeneration (reviewed in [40]).”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [40]
The Clinical studies of immune dysregulation section reports CD8+ T cells in the CSF and hippocampi of patients with AD, and the Mechanistic insight from animal studies section reports T-cell infiltration in AD brain parenchyma. But the review does not establish that both CD4+ and CD8+ cells are present in both locations or that they have been shown to cause neurodegeneration in patients. It says their functional significance needs further study, while mouse studies show both beneficial and detrimental effects. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThere are multiple mechanisms for peripheral and central immune communication, including direct pathways of peripheral immune cell infiltration across the BBB and indirect pathways of systemic inflammation-driven modulation of CNS microglial function.
“Although the blood-brain barrier (BBB) protects the brain, there are multiple mechanisms for peripheral and central immune communication, including direct pathways of peripheral immune cell infiltration across the BBB and indirect pathways of systemic inflammation-driven modulation of CNS microglial function. (350, 351)”
From Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission (2024) · cites this paper as [350]
Inflammation, especially neuroinflammation, accompanies AD pathological processes and is linked to cognitive deficits.
“Moreover, inflammation, especially neuroinflammation, accompanies AD pathological processes and is also linked to cognitive deficits.”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [15]
Inflammatory responses, especially neuroinflammation, accompany the entire progress of AD pathogenesis and are linked to cognitive dysfunction.
“The inflammatory responses (especially neuroinflammation) accompany the entire progress of AD pathogenesis and are also linked to cognitive dysfunction [15].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [15]
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References 165 · Cited by 427
- Authors
- Bettcher, B. M., Tansey, M. G., Dorothée, G., & Heneka, M. T.
- Affiliations
- University of Colorado Anschutz (US)
- University of Florida Health (US)
- Inserm (FR)
- University of Bonn (DE)
- Corresponding author
- Bettcher, Brianne M.
- Venue
- Nature Reviews Neurology
- Published
- 2021-09-14
- Volume
- 17
- Issue
- 11
- Pages
- 689-701
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- PMC
- PMC8439173
- OpenAlex
- W3199972090
- Cited by
- 427
- References
- 165
- Citations by year
- 2026: 78 · 2025: 81 · 2024: 105 · 2023: 91 · 2022: 68 · 2021: 3
- FWCI
- 7.94
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-10-08)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- eScholarship@UMassChan (submittedVersion)
- HAL (submittedVersion)
- Funders
- U.S. Department of Defense
- Michael J. Fox Foundation for Parkinson's Research
- Alzheimer's Association
- Parkinson's Foundation
- Fondation Vaincre Alzheimer
- Deutsche Forschungsgemeinschaft (R01 AG059752-02)
- National Institutes of Health
- National Institute on Aging (RF1AG057247, R01AG059752, R01AG058772)
- National Institute of Neurological Disorders and Stroke (RF1NS128800)
- Congressionally Directed Medical Research Programs
- 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, neuroinflammation, systemic immune response, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Humans, Immune System, Research
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