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Systemic inflammation and disease progression in Alzheimer disease
Open accessAbstract
BACKGROUND: Acute and chronic systemic inflammation are characterized by the systemic production of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) that plays a role in immune to brain communication. Previous preclinical research shows that acute systemic inflammation contributes to an exacerbation of neurodegeneration by activation of primed microglial cells. OBJECTIVE: To determine whether acute episodes of systemic inflammation associated with increased TNF-alpha would be associated with long-term cognitive decline in a prospective cohort study of subjects with Alzheimer disease. METHODS: Three hundred community-dwelling subjects with mild to severe Alzheimer disease were cognitively assessed, and a blood sample was taken for systemic inflammatory markers. Each subject's main caregiver was interviewed to assess the presence of incident systemic inflammatory events. Assessments of both patient and caregiver were repeated at 2, 4, and 6 months. RESULTS: Acute systemic inflammatory events, found in around half of all subjects, were associated with an increase in the serum levels of proinflammatory cytokine TNF-alpha and a 2-fold increase in the rate of cognitive decline over a 6-month period. High baseline levels of TNF-alpha were associated with a 4-fold increase in the rate of cognitive decline. Subjects who had low levels of serum TNF-alpha throughout the study showed no cognitive decline over the 6-month period. CONCLUSIONS: Both acute and chronic systemic inflammation, associated with increases in serum tumor necrosis factor alpha, is associated with an increase in cognitive decline in Alzheimer disease.
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“Systemic inflammation induced by the activation of Toll-like receptors (TLRs) and inflammatory mediators such as TNFα has been suggested to cause cognitive decline and accelerate the progression of Alzheimer’s disease (Squillace and Salvemini 2022; Holmes et al. 2009).”
From Astrocyte-specific inhibition of the primary cilium suppresses C3 expression in reactive astrocyte (2024) · cites this paper as Holmes et al. 2009
In the citing paper
“which is accelerated by systemic infections, including gum disease.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [73]
In the citing paper
“For example, systemic infections accelerate cognitive decline in Alzheimer’s disease patients [73]”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [73]
In the citing paper
“Some studies have reported inflammatory challenges as an associated risk factor for the development of dementia-related symptoms, as they show increased pro-inflammatory cytokines levels [147, 148].”
From Brain-Derived Neurotrophic Factor in Brain Disorders: Focus on Neuroinflammation (2019) · cites this paper as [148]
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Barberger‐Gateau, P., Samieri, C., Féart, C., & Plourde, M. (2011) · Current Alzheimer Research · doi:10.2174/156720511796391926 · Cited by 133
“Acute systemic inflammation is also suspected to exacerbate chronic brain inflammation thereby increasing the rate of cognitive decline in AD patients [45].”
BackgroundTargeting innate immunity for neurodegenerative disorders of the central nervous system
Andreasson, K. I., Bachstetter, A. D., Colonna, M., Ginhoux, F., Holmes, C., Lamb, B., Landreth, G., Lee, D. C., Low, D., Lynch, M. A., et al. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13667 · Cited by 126
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“TNF-α, a pro-inflammatory cytokine, is a common component of inflammatory signaling in AD [60] and T2DM and obesity [61].”
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“Chronic inflammation has detrimental effects on the brain and is an important part of chronic neurodegenerative disorders (Holmes et al., 2009; Najem, Bamji-Mirza, Chang, Liu, & Zhang, 2014).”
Background18F-GE-180: a novel TSPO radiotracer compared to 11C-R-PK11195 in a preclinical model of stroke
Boutin, H., Murray, K. N., Pradillo, J. M., Maroy, R., Smigova, A., Gerhard, A., Jones, P. A., & Trigg, W. (2014) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-014-2939-8 · Cited by 125
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Systemic inflammation linking chronic periodontitis to cognitive decline
Wang, R. P., Ho, J. Y. S., Leung, W. K., Goto, T., & Chang, R. C. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.07.002 · Cited by 129
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“Neuroinflammation is an important hallmark of brain pathology (Akiyama et al , 2000), and both acute and chronic inflammation are associated with cognitive decline (Holmes et al , 2009).”
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Satapathy, S. K., Ochani, M., Dancho, M. E., Hudson, L., Rosas‐Ballina, M., Valdés‐Ferrer, S. I., Olofsson, P. S., Harris, Y., Roth, J., Chavan, S. S., et al. (2011) · Molecular Medicine · doi:10.2119/molmed.2011.00083 · Cited by 119
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“A link between common infections and clinical progression in Alzheimer’s disease has been demonstrated.(9) These studies suggest that systemic infections contribute to brain disease by promoting activation of the immune system.”
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Plantone, D., Pardini, M., Righi, D., Manco, C., Colombo, B. M., & Stefano, N. D. (2023) · Cells · doi:10.3390/cells13010054 · Cited by 125
“A 6-month study exploring the association between TNF-α levels and cognitive performance in 300 subjects with varying AD severity, found that acute inflammation correlated with a twofold cognitive decline increase, and high-baseline TNF-α levels quadrupled the decline [98].”
BackgroundThe role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap
Walker, K. A., Page, L. M. L., Terrando, N., Duggan, M. R., Heneka, M. T., & Bettcher, B. M. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00627-2 · Cited by 121
“The immune response to acute insults is tightly regulated and temporally limited in younger adults, whereas in older adults the response to acute insults may be more protracted [18, 36, 37] and thus more likely to initiate or catalyze ongoing degenerative processes [38].”
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The role of the immune system in Alzheimer’s disease
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Innate Inflammation in Parkinson's DiseasePreprint
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“Clinical studies in patients with Alzheimer’s disease show an association between acute and chronic systemic inflammation and accelerated cognitive decline (Holmes et al. 2009) and increased frequency of behavioral symptoms typical of sickness behavior (Holmes et al.”
BackgroundSelf-citationOsteoarthritis accelerates and exacerbates Alzheimer's disease pathology in mice
Kyrkanides, S., Tallents, R. H., Miller, J. H., Olschowka, M. E., Johnson, R. E., Yang, M., Olschowka, J. A., Brouxhon, S. M., & O’Banion, M. K. (2011) · Journal of Neuroinflammation · doi:10.1186/1742-2094-8-112 · Cited by 116
“Peripheral inflammation as a risk factor for AD was previously suggested by several clinical [1-6] and animal studies.”
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“The chronic inflammation response in the brain plays a key role in the progression of neurodegenerative disorders [59], and a reduction of this process most likely also plays a part in the overall improvement of the”
BackgroundPro‐inflammatory activation of microglia in the brain of patients with sepsis
Zrzavy, T., Höftberger, R., Berger, T., Rauschka, H., Butovsky, O., Weiner, H. L., & Lassmann, H. (2018) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12502 · Cited by 115
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Mechanisms of neurodegeneration shared between multiple sclerosis and Alzheimer’s disease
Lassmann, H. (2011) · Journal of Neural Transmission · doi:10.1007/s00702-011-0607-8 · Cited by 112
“On the other hand, recent studies suggest that concomitant systemic infections are associated with more rapid disease progression in AD (Holmes et al. 2009).”
BackgroundThe effect of systemic inflammation on human brain barrier function
Elwood, E., Lim, Z., Naveed, H., & Galea, I. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.10.020 · Cited by 109
“Systemic infection causes accelerated cognitive decline in patients with AD (Holmes et al., 2009) and impairs outcome in stroke patients (Smith et al.”
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Systemic and CNS Inflammation Crosstalk: Implications for Alzheimer’s Disease
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“Peripheral inflammation and elevated systemic cytokine levels have been proposed to contribute to brain inflammation and pathogenesis in Alzheimer’s disease (14,15), Parkinson’s disease (16) and schizophrenia (17).”
Background
Metadata
- Authors
- Holmes, C., Cunningham, C., Zotova, E., Woolford, J., Dean, C., Kerr, S., Culliford, D., & Perry, V. H.
- Affiliations
- Trinity College Dublin (IE)
- Venue
- Neurology
- Published
- 2009-09-08
- Volume
- 73
- Issue
- 10
- Pages
- 768-774
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC2848584
- OpenAlex
- W2085558085
- Semantic Scholar
- cbac9326b978c2365dec0a3f265816a795105bb1
- Cited by
- 1,139
- References
- 42
- Citations by year
- 2026: 48 · 2025: 68 · 2024: 85 · 2023: 75 · 2022: 77 · 2021: 87 · 2020: 84 · 2019: 89 · 2018: 71 · 2017: 71 · 2016: 59 · 2015: 67 · 2014: 57 · 2013: 55 · 2012: 58
- FWCI
- 29.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- Wellcome Trust (078300)
- National Institute for Health and Care Research
- National Institutes of Health (5rc2ag036502-02)
- Biotechnology and Biological Sciences Research Council
- National Institute on Aging (R01AG012101)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, systemic inflammation, TNF-α, cognitive decline, disease progression, neuroinflammation, microglial activation, inflammatory cytokines, serum biomarkers
- MeSH terms
- Acute Disease, Aged, Aged, 80 and over, Alzheimer Disease, Chronic Disease, Cognition Disorders, Female, Follow-Up Studies, Humans, Male, Prospective Studies, Retrospective Studies, Tumor Necrosis Factor-alpha, Cohort Studies, Biomarkers, Disease Progression, Inflammation Mediators
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