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 activation of TLRs and inflammatory mediators such as TNFα causes cognitive decline and accelerates progression of Alzheimer's disease.
“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
Alzheimer's disease is accelerated by systemic infections, including gum disease.
“which is accelerated by systemic infections, including gum disease.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [73]
Systemic infections accelerate cognitive decline in Alzheimer's disease patients.
“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]
Inflammatory challenges are associated with risk for development of dementia-related symptoms, with increased pro-inflammatory cytokine levels.
“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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- 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
- Health Sciences › Medicine › Physiology › 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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