The DOI matches its Crossref record; 40 of the 42 references it cites were found in a registry or an index.
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
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“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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BackgroundZhu, X., Hao, R., Lv, X., Su, J., Li, D., & Zhang, C. (2024) · Food Frontiers · doi:10.1002/fft2.365 · Cited by 8
Aretz, B., Doblhammer, G., & Heneka, M. T. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14320 · Cited by 9
Xu, X., Wei, S., Lin, M., Chen, F., Zhang, X., & Zhu, Y. (2024) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2024.2440602 · Cited by 9
“Systemic inflammation originating from the gut has the potential to exacerbate the onset and progression of neurodegenerative diseases (Brudek 2019; Holmes et al. 2009; Liu et al. 2020).”
Yamanashi, T., Sullivan, E. J., Comp, K. R., Nishizawa, Y., Akers, C. C., Chang, G., Modukuri, M., Tran, T., Anderson, Z. M., Marra, P. S., et al. (2023) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2023.111212 · Cited by 8
Preventive strategies and potential therapeutic interventions for delirium in sepsis
de Souza-Dantas, V. C., Póvoa, P. M. S. R., Bozza, F. A., Soares, M., & Salluh, J. I. (2016) · Hospital Practice · doi:10.1080/21548331.2016.1192453 · Cited by 8
“hypothesized to contribute too.[62] Neurocognitive impairment occurs in a variety of domains, but in general, in sepsis, predominantly affected the left hippocampus.”
BackgroundEtanercept in Alzheimer disease: A randomized, placebo-controlled, double-blind, phase 2 trial
(2015) · Neurology · doi:10.1212/wnl.0000000000002206 · Cited by 8
High Mobility Group Box 1 Ameliorates Cognitive Impairment in the 3×Tg-AD Mouse Model
Zhang, J. C., Hua, X., Gu, J., Chen, F., Gu, J., Gong, C., Liu, F., & Dai, C. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-191110 · Cited by 8
Pentoxifylline suppressed LPS-induced inflammatory and apoptotic signaling in neuronal cells
Muchhala, S., & Benzeroual, K. E. (2012) · Advances in Bioscience and Biotechnology · doi:10.4236/abb.2012.326094 · Cited by 8
“Pro-inflammatory cytokines such as TNF-α have been reported to contribute to neurodegenerative disorders initiation and progression [35,36], and have been involved as cellular stimulators of apoptotic pathways [37, 38].”
General Physiology and Pathophysiology of Microglia During Neuroinflammation
Patro, I. K., Nagayach, A., Sinha, S., & Patro, N. (2016) · Springer eBooks · doi:10.1007/978-981-10-1711-7_2 · Cited by 8
“…in various cross-sectional and prospective population studies, it was shown that any alteration in the level of these cytokines in hippocampus lead to Alzheimer’s disease (AD), dementia and cognitive impairment (Dik et al. 2005; Magaki et al. 2007; Holmes et al. 2009; Brosseron et al. 2014).”
BackgroundJulian, A., Bilan, A. R., Ragot, S., Krolak‐Salmon, P., Berrut, G., DANTOINE, T. F., Hommet, C., Hanon, O., Page, G., & Paccalin, M. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-171131 · Cited by 8
Innate Immune Tolerance in Microglia Does Not Impact on Central Nervous System Prion Disease
Pal, R., Bradford, B. M., & Mabbott, N. A. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.918883 · Cited by 7
Solleiro-Villavicencio, H., & Rivas-Arancibia, S. (2019) · Neurología (English Edition) · doi:10.1016/j.nrleng.2019.03.003 · Cited by 7
Clinical implication of anemia in older patients with dementia with lewy bodies
Karışmaz, A., Soysal, P., Eren, R., Serin, İ., Bilgiç, İ., Tanriverdi, I., & Smith, L. (2025) · Aging Clinical and Experimental Research · doi:10.1007/s40520-025-02958-0 · Cited by 7
“Although there was no difference in comorbid conditions between the groups with and without anemia, except for CHF, inflammation present in dementia may also be a con - tributing factor to the development of anemia [ 40 ].”
Lim, V. J. T., Tabassum, N. I., Orian, J. M., Arumugam, T. V., & Weng, E. F.-J. (2025) · Progress in brain research · doi:10.1016/bs.pbr.2025.05.003 · Cited by 7
Ajith, T. A., & Sreejith, J. K. (2025) · Nutritional Neuroscience · doi:10.1080/1028415x.2025.2567429 · Cited by 7
“Experimental and clinical evidence has demonstrated that events involving acute/chronic systemic inflammation from infections increase the serum TNF-α levels, which subsequently results in neuroinflammation and exacerbates cognitive loss [79,80].”
Stanbouly, D., Zeng, Q., Jou, Y.-T., & Chuang, S. (2022) · Frontiers of Oral and Maxillofacial Medicine · doi:10.21037/fomm-21-117 · Cited by 7
Grifola frondosa polysaccharides alleviate Alzheimer's disease in rats
Behrad, S., Pourranjbar, S., Pourranjbar, M., Abbasi-Maleki, S., Mehr, S. R., Salmani, R. H. G., & Moradikor, N. (2024) · Asian Pacific Journal of Tropical Biomedicine · doi:10.4103/apjtb.apjtb_294_24 · Cited by 7
Wang, K., Liu, Y., Shaoqing, G., Xu, C. D., Xie, X., Wang, L., & Xingguang, L. (2017) · International Journal of Clinical Biostatistics and Biometrics · doi:10.23937/2469-5831/1510014 · Cited by 6
Tumor Necrosis Factor-Alpha Alters Electrophysiological Properties of Rabbit Hippocampal Neurons
Wang, D. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190043 · Cited by 7
The Risk of Alzheimer's Disease After Acute Appendicitis With or Without Appendectomy
Liang, C., Bai, Y., Hsu, J.-W., Huang, K., Chu, C., Yeh, T., Tsai, S., Chen, T., & Chen, M. (2021) · Journal of the American Medical Directors Association · doi:10.1016/j.jamda.2021.06.013 · Cited by 7
Association between Insulin Resistance and Cognitive Impairment
Chen, M., Zhang, M., Wang, S., Ding, X., Lee, Y., & Jiang, G. (2022) · Journal of College of Physicians And Surgeons Pakistan · doi:10.29271/jcpsp.2022.02.202 · Cited by 7
Non-Communicable Neurological Disorders and Neuroinflammation
Ballerini, C., NJAMNSHI, A. K., Juliano, S. L., Kalaria, R. N., Furlan, R., & Akinyemi, R. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.834424 · Cited by 7
“This finding does not indicate a direct cause-effect relation with AD, however it may indicate a link between infections with progressive neurodegeneration and rapid cognitive decline (106).”
ResultSheikh, W. G. E., Sleem, B., Kobeissy, F. H., & Bizri, M. (2023) · Biomarkers in Neuropsychiatry · doi:10.1016/j.bionps.2023.100064 · Cited by 10
The loss of neural synchrony in the post septic brain
Götz, T., Baumbach, P., Reuken, P. A., Huonker, R., Kranczioch, C., Debener, S., Brunkhorst, F. M., Witte, O. W., Klingner, C. M., & Günther, A. (2016) · Clinical Neurophysiology · doi:10.1016/j.clinph.2016.02.006 · Cited by 7
“It is well established that inflammation plays a significant role in the progression of neurodegeneration (DeLegge et al., 2008; Holmes et al., 2009; Iwashynaet al., 2010;Gunther et al., 2012;Cunningham, 2013; Pandharipande et al., 2013; Shah et al., 2013).”
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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