Cited by 1,139Dementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatments

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Systemic inflammation and disease progression in Alzheimer disease

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Holmes, C., Cunningham, C., Zotova, E., Woolford, J., Dean, C., Kerr, S., Culliford, D., Perry, V. H.·2009·Neurology

DOI 10.1212/wnl.0b013e3181b6bb95PMC PMC2848584

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Abstract

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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“In particular in the case of Alzheimer’s disease inflammatory involvement has been described both in neuropathological and epidemiological studies (KAMER et al., 2008; HOLMES et al., 2009).”
Background
The ME7 prion model of neurodegeneration as a tool to understand and target neuroinflammation in Alzheimer’s disease
Chouhan, J. K., Fowler, S. A., Webster, C. I., & Teeling, J. L. (2017) · Drug Discovery Today Disease Models · doi:10.1016/j.ddmod.2018.10.004 · Cited by 4
Processo Inflamatório e Neuroimunomodulação na Doença de Alzheimer
Rocha, N. P., Martins, L. D. C. A., Teixeira, A. L., & Reis, H. J. (2001) · Revista Neurociências · doi:10.34024/rnc.2011.v19.8385 · Cited by 24
Many Paths to Alzheimer’s Disease: A Unifying Hypothesis Integrating Biological, Chemical, and Physical Risk Factors
Lehmann, D. J., Elshorbagy, A. K., & Hurley, M. J. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230295 · Cited by 5
“A greater understanding of the many potential causes of AD should lead to the development of strategies to prevent AD and perhaps even lead to the identiﬁcation of effective measures that will treat AD.”
The RESIST Study: Examining Cognitive Change in Rheumatoid Arthritis Patients with Mild Cognitive Impairment Being Treated with a TNF-Inhibitor Compared to a Conventional Synthetic Disease-Modifying Anti-Rheumatic Drug
Marr, C., McDowell, B., Holmes, C., Edwards, C. J., Cardwell, C. R., McHenry, M., Meenagh, G., Teeling, J. L., & McGuinness, B. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-231329 · Cited by 4
Self-citation
Reducing dietary lipopolysaccharides to slow progression of cognitive impairment and Alzheimer’s disease
Blake, S. M., Baroni, L., Blake, C. P., Harding, T., Piboolnurak, P., Harding, M., & Grant, W. B. (2024) · Journal of Brain Sciences · doi:10.18488/83.v7i1.3801 · Cited by 4
“It can be hypothesized that in AD, acute systemic inflammation associated with increased TNF α can lead to increased cognitive decline (Holmes et al., 2009).”
Background
Aging Microglia and Their Impact in the Nervous System
Rommy von Bernhardi, M., & Eugenín, J. L. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-55529-9_21 · Cited by 4
Association between neurodegenerative diseases and pneumonia: a retrospective population-based study
Yeh, J., Lin, C., Hsu, C. Y., Shae, Z., & Kao, C. (2018) · Current Medical Research and Opinion · doi:10.1080/03007995.2018.1552408 · Cited by 4
“10 in the ND cohort compared to the non-ND cohort; (2) consistency – the result is observed in the different groups such as in the different age and sex groups, and those with second and later episodes of pneumonia after the initial episode of atypical or typical pneumonia in this study; (3) specificity – the risk of…”
Result
Association Between Cognitive Decline and Oral Health Status in the Aging Population
Bumb, S. S., Govindan, C. C., Kadtane, S. S., Chawla, R. M., Gupta, R., & Khoriya, S. S. (2021) · GeroPsych · doi:10.1024/1662-9647/a000271 · Cited by 4
A novel co-culture model for investigation of the effects of LPS-induced macrophage-derived cytokines on brain endothelial cells
Yang, J., Li, Y., Bhalla, A., Maienschein‐Cline, M., & Fukuchi, K.-I. (2023) · PLoS ONE · doi:10.1371/journal.pone.0288497 · Cited by 5
Neuroinflammation in Alzheimer's disease
Agrawal, M., Singhal, M., Prajapati, B. G., Chaudhary, H., Jasoria, Y., Kumar, B., Arora, M. K., & Sahoo, J. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-13205-6.00003-0 · Cited by 4
Gene–physical activity interactions in lower extremity performance: inflammatory genes CRP, TNF-α, and LTA in community-dwelling elders
Liu, C.-S., Li, T., Li, C., Liao, L.-N., Yang, C., Lin, C., Meng, N., Lin, W., Hu, S., Hsiao, J.-H., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-03077-1 · Cited by 4
The Enteric Glial Network Acts in the Maintenance of Intestinal Homeostasis and in Intestinal Disorders
Coelho‐Aguiar, J. D. M., Veríssimo, C. P., Costa, D. V. D. S., Thomasi, B. B. D. M., Bon‐Frauches, A. C., Ribeiro, F. P., Gomes, A. L. T., Brito, G. A. D. C., & Moura‐Neto, V. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.89170 · Cited by 8
“[145] Holmes C, Cunningham C, Zotova E, Woolford J, Dean C, Kerr S, et al.”
A Knowledge-based Integrative Modeling Approach for In-Silico Identification of Mechanistic Targets in Neurodegeneration with Focus on Alzheimer's Disease
Younesi, E. (2014) · Cited by 4
Mitochondria at the Base of Neuronal Innate Immunity in Alzheimer’s and Parkinson’s Diseases
Esteves, A. R., Silva, D. F., Santos, D., Candeias, E., Filipe, F., & Cardoso, S. M. (2018) · InTech eBooks · doi:10.5772/intechopen.72612 · Cited by 4
“the other hand,systemic inflammation may be induced from several chronic diseases [135], such as obesity and T2D, all characterized by CNS inflammation and microglia activation [136, 137].”
Background
Cognitive Impairment in Parasitic Protozoan Infection
Chakroborty, N. K., Baksi, S., & Bhattacharya, A. (2023) · Springer eBooks · doi:10.1007/978-981-19-8225-5_4 · Cited by 3
Association Between Receipt of Ketamine vs Etomidate for Emergency Tracheal Intubation and Symptoms of Posttraumatic Stress Disorder at 12 Months
Wollenman, L. C., Tipold, A. M., Semler, M. W., Casey, J. D., Lacy, A. J., Self, W. H., Kiehl, A. L., Bryant, P. T., DeMasi, S. C., Stanley, I. H., et al. (2025) · CHEST Critical Care · doi:10.1016/j.chstcc.2025.100136 · Cited by 4
Infections and cognitive function, depression, and frailty: a cross-sectional study in the longitudinal aging study in India (LASI)
Gore‐Langton, G. R., Mansfield, K. E., Ravi, P., Doubatty, A., Alladi, S., Kinra, S., & Warren‐Gash, C. (2025) · BMC Public Health · doi:10.1186/s12889-025-23490-w · Cited by 3
“While biologically plausible that non-CNS infections are detrimental to brain health, via systemic inflammation [5, 6] the links are less well understood.”
Associations between plasma proteins and psychological wellbeing: evidence from over 20 years of the English Longitudinal Study of Ageing
Gong, J., Scholes, S., Cole, S., Zaninotto, P., & Steptoe, A. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03401-6 · Cited by 4
Tryptophan–kynurenine metabolic reprogramming along the gut–brain axis alleviates Alzheimer’s pathology
Choi, H., Hong, S. B., Kim, Y., Joung, H., Choi, Y., Cha, J., Park, J. Y., Lee, Y.-S., Choi, H., Han, J. W., et al. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03796-1 · Cited by 3
“4K), consistent with prior literature linking elevated TNF-α, systemic inflammatory burden to accelerated cognitive decline [54].”
Amyloidopathy in the Eye of Alzheimer′s Disease
Zhang, X. (2011) · Journal of Addiction Research & Therapy · doi:10.4172/2155-6105.s5-005 · Cited by 3
“Increasing evidence shows that AD is characterized by a systemic inflammation [34-36], which accompanies the course of cognitive decline.”
Background
Chronic Airway Allergy Induces Pro-Inflammatory Responses in the Brain of Wildtype Mice but Not 3xTgAD Mice
Sarlus, H., Codita, A., Wang, X., Cedazo-Mı́nguez, Á., Schultzberg, M., & Oprica, M. (2020) · Neuroscience · doi:10.1016/j.neuroscience.2020.09.005 · Cited by 3
Perfusion Imaging and Inflammation Biomarkers Provide Complementary Information in Alzheimer’s Disease
Michopoulou, S. K., Prosser, A. M. J., Dickson, J. C., Guy, M., Teeling, J. L., & Kipps, C. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230726 · Cited by 3
Highlighting the Effect of Pro-inflammatory Mediators in the Pathogenesis of Periodontal Diseases and Alzheimer’s Disease
Hashim, N. T., Babiker, R. A., Mohammed, R., Chaitanya, N. C., Rahman, M. M., & Gismalla, B. G. (2024) · Journal of Pharmacy And Bioallied Sciences · doi:10.4103/jpbs.jpbs_1120_23 · Cited by 4
“[31,32] In individuals with AD, elevated IL‑1 β predicted rates of cognitive decline.”
Extraction Condition Optimization, Quantitative Analysis, and Anti-AD Bioactivity Evaluation of Acorn Polyphenols from Quercus variabilis, Quercus aliena, and Quercus dentata
Du, J., Han, Z., Ran, L., Zhang, T., Li, J., & Li, H. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms251910536 · Cited by 3
“This inflammatory process is believed to amplify the neurodegenerative effects of A β , creating a vicious cycle that accelerates the progression of AD [17].”
Background
CT1812, a Small Molecule Sigma-2 Receptor Antagonist for Alzheimer’s Disease Treatment: A Systematic Review of Available Clinical Data
Thitilertdecha, P., & Brimson, J. M. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-230994 · Cited by 3
Systemic Inflammatory Factors and Neuropsychiatric Disorders: A Bidirectional Mendelian Randomization Study
Wang, H., Cheng, Z., Xu, Z., Wang, M., Sun, X., Liu, W., Wang, J., Yang, Q., Zhang, T., Song, J., et al. (2025) · Brain and Behavior · doi:10.1002/brb3.70478 · Cited by 3
Metabolic and Immune Risk Factors for Dementia and their Modification by Flavonoids: New Targets for the Prevention of Cognitive Impairment?
Saunders, C., & Spencer, J. P. E. (2012) · Nutrition and Aging · doi:10.3233/nua-2012-0008 · Cited by 3
“In a cohort of 300 AD patient’s, a high baseline plasma concentration of TNF- was found to be associated with a 4-fold increase in the rate of cognitive decline over a 6-month period [43].”
Background
Are tumour necrosis factor inhibitor drugs associated with a lower risk of dementia?
Zafeiridi, E., McMichael, A., Mirakhur, A., McHenry, M., Holmes, C., & McGuinness, B. (2020) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.5297 · Cited by 3
“shown to be associated with a greater rate of cognitive decline in subjects with AD; it is hypothesised that this is because of a systemic pro-inflammatory state notably the presence of raised serum levels of tumour necrosis factor (TNFα).(1) Past research has also shown that the use of the peripheral tumour necrosis…”
ResultSelf-citation
The Impact of Uremic Toxins on Alzheimer's Disease
Zheng, Y., Ji, B., Chen, S., Zhou, R., & Ni, R. (2022) · Current Alzheimer Research · doi:10.2174/1567205019666220120113305 · Cited by 3
In vivo molecular imaging of the neuroinflammatory response to peripheral acute bacterial infection in older patients with cognitive dysfunction: A cross-sectional controlled study
Silva, A. R., Regueira, P., Peres, A. S. C., Cardoso, A. L., Baldeiras, I., Santana, I. J., & Cerejeira, J. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.984178 · Cited by 3
“Acute systemic inflammatory events have been associated with a 2-fold increase in the rate of cognitive decline over a 6-month period (Norden and Godbout, 2013) and patients with AD who experienced an infection and/or delirium have accelerated cognitive decline (Fong et al., 2009; Holmes et al., 2009).”
Background
The effect of the tumour necrosis factor-alpha-inhibitor etanercept on microglial activation patients with mild cognitive impairment—a PET study
Gerhard, A., Sharples, R., Goerttler, T., McDonald, K. R., Visi, E., Hinz, R., Turkheimer, F., Lewzey, I., Herholz, K., Jacobs, A. H., et al. (2023) · Exploration of neuroscience · doi:10.37349/en.2023.00012 · Cited by 3
Self-citation
Non-Genetic Risk Factors for Dementia and Alzheimer’s Disease
Bazzari, F. H., & Bazzari, A. H. (2023) · Jordan Medical Journal · doi:10.35516/jmj.v57i3.1673 · Cited by 3
“Both acute and chronic inflammatory episodes that elevate tumor necrosis factor-α (TNF-α) are found to accelerate AD-related cognitive decline [129].”
Association between statin compliance and risk of dementia among patients with chronic periodontitis
Kim, Y., Son, M., & Kim, S. (2023) · Oral Diseases · doi:10.1111/odi.14784 · Cited by 3
Case report: Cerebral amyloid angiopathy-related inflammation in a patient with granulomatosis with polyangiitis
Seifert, R. M., Rauch, M., Klingebiel, R., Boese, L.-M., Greeve, I., Rudwaleit, M., & Schäbitz, W. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1277843 · Cited by 3
Osteoclasts Link Dysregulated Peripheral Degradation Processes and Accelerated Progression in Alzheimer’s Disease
Wu, B., Chen, M., Meng, L., Tian, Q., & Dong, Z. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-240096 · Cited by 4
No association between markers of systemic inflammation and endothelial dysfunction with Alzheimer’s disease progression: a longitudinal study
van Setten, A., Uleman, J. F., Melis, R. J. F., LAWLOR, B. A., Riksen, N. P., Claassen, J. A. H. R., de Heus, R. A. A., on behalf of NILVAD Study Group, Segurado, R., Kennelly, S., et al. (2024) · GeroScience · doi:10.1007/s11357-024-01294-x · Cited by 3
“Secondly, although we found comparable inflammation levels with several studies of AD patients [1, 23, 32, 64], other comparable studies found higher inflammation levels for TNF-α and IL-1ß [6, 18, 24, 40, 73].”
Secondary immunodeficiency (immune paralysis) following spinal cord injury
Brommer, B., Kopp, M. A., Laginha, I., & Schwab, J. M. (2010) · e-Neuroforum · doi:10.1007/s13295-010-0008-8 · Cited by 3
Biochemical and Radiological Markers of Alzheimer’s Disease Progression
Dziedzic, T., Pera, J., Klimkowicz‐Mrowiec, A., Mroczko, B., & Słowik, A. (2016) · Journal of Alzheimer s Disease · doi:10.3233/ifs-150578 · Cited by 3
Influence of CRP on cognitive function of patients with combined and isolated forms of atherosclerosis of cerebral and coronary vascular pools
Bilyutin-Aslanyan, R. S., & Vasiliev, A. G. (2017) · Pediatrician (St Petersburg) · doi:10.17816/ped8680-85 · Cited by 3
Pathogenesis and Therapeutic Strategies in Alzheimer’s Disease: From Brain to Periphery
Yu, J., & Zhang, C. M. (2015) · Neurotoxicity Research · doi:10.1007/s12640-015-9576-2 · Cited by 3
“This study is also consistent with the evidence from epidemiological studies, showing that AD is highly associated with systemic diseases such as Type II diabetes, hypertension, obesity, systemic inflam- matory diseases and kidney failure (Holmes et al. 2009; Li et al. 2011; Xu et al. 2015).”
Result
Toll-Like Receptors (TLRs) in Neurodegeneration: Integrative Approach to TLR Cascades in Alzheimer’s and Parkinson’s Diseases
Zolezzi, J. M., Candia, S. B., & Inestrosa, N. C. (2019) · IntechOpen eBooks · doi:10.5772/intechopen.86167 · Cited by 3

Authors: Holmes, C., Cunningham, C., Zotova, E., Woolford, J., Dean, C., Kerr, S., Culliford, D., & Perry, V. H.
Affiliations: Trinity College Dublin (IE)
ORCID: Holmes, C.
Cunningham, C.
Culliford, D.
Perry, V. H.
Venue: Neurology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2009-09-08
Volume: 73
Issue: 10
Pages: 768-774
ISSN: 0028-3878 (ISSN-L)
1526-632X
DOI: 10.1212/wnl.0b013e3181b6bb95
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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Systemic inflammation and disease progression in Alzheimer disease

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