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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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“Indeed cognitive decline has been observed just 2 or 6 months after a resolved peripheral infection, with an association between cognitive impairment and circulating proinflammatory cytokines [19, 20].”
BackgroundInflammation and Adaptive Immunity in Parkinson's DiseasePreprint
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“Peripheral immune responses can trigger inflammation and exacerbation of CNS degeneration in several neurodegenerative diseases such as Alzheimer’s disease (AD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), stroke, and prion-mediated diseases (Cunningham et al. 2005a,b; Kamer et al. 2008; Fiala and Ve…”
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“…with an increased serum level of tumor necrosis factor-a was shown to lead to a 2-fold increase in the rate of cognitive decline over a 6-month period, which has been suggested to originate from a higher response of primed microglia upon peripheral in fl ammatory signal (Holmes et al., 2009).”
Nutrition for the ageing brain: Towards evidence for an optimal diet
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“The group of Perry et al. has demonstrated that systemic inflammation and acute infections are associated with an enhanced rate of cognitive decline (Holmes et al., 2009) and increased symptoms of sickness in AD patients (Holmes et al., 2011).”
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“Tumor necrosis factor alpha (TNF-α) has been associated with cognitive decline, [111] and both TNF-α and another inflammatory molecule, IL-1β, have been associated with increased AD risk.”
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“IL-4 inhibits the secretion of IL-1, IL-6 and TNF- by activated monocytes (75).”
InfluentialPorphyromonas gingivalis Periodontal Infection and Its Putative Links with Alzheimer’s Disease
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“Persisting chronic peripheral/intrinsic inflammation is hypothesised to affect BBB capillary wall which likely prevents efflux of soluble/insoluble A𝛽 from the CNS.”
InfluentialThe capillary dysfunction hypothesis of Alzheimer's disease
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“This is in agreement with observations that systemic inflammation aggravates the disease (Holmes et al., 2009), and reports of a higher prevalence of chronic infections in AD (Fotuhi et al., 2009).”
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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