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

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 access

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

Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1212/wnl.0b013e3181b6bb95

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Clinical diagnosis of Alzheimer's disease: Report of the NINCDS‐ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915
Special Care Units and Traditional Care in Dementia: Relationship with Behavior, Cognition, Functional Status and Quality of Life - A Review
Kok, J. S., Berg, I. J., & Scherder, E. J. A. (2013) · Dementia and Geriatric Cognitive Disorders Extra · doi:10.1159/000353441 · Cited by 20,589
Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: A Statement for Healthcare Professionals From the Centers for Disease Control and Prevention and the American Heart Association
Pearson, T. A., Mensah, G. A., Alexander, R. W., Anderson, J. L., Cannon, R. O., Criqui, M., Fadl, Y. Y., Fortmann, S. P., Hong, Y., Myers, G. L., et al. (2003) · Circulation · doi:10.1161/01.cir.0000052939.59093.45 · Cited by 6,401
Clarifying Confusion: The Confusion Assessment Method: A New Method for Detection of Delirium
Inouye, S. K., van Dyck, C. H., Alessi, C. A., Balkin, S., Siegal, A. P., & Horwitz, R. I. (1990) · Annals of Internal Medicine · doi:10.7326/0003-4819-113-12-941 · Cited by 5,250
A new rating scale for Alzheimer's disease
(1984) · American Journal of Psychiatry · doi:10.1176/ajp.141.11.1356 · Cited by 4,175
MARKERS OF INFLAMMATION AND CARDIOVASCULAR DISEASE: APPLICATION TO CLINICAL AND PUBLIC HEALTH PRACTICE: A STATEMENT FOR HEALTHCARE PROFESSIONALS FROM THE CENTERS FOR DISEASE CONTROL AND PREVENTION AND THE AMERICAN HEART ASSOCIATION
PearsonT, A., MensahG, A., & AlexanderR, W. (2003) · Journal of Cardiopulmonary Rehabilitation · doi:10.1097/00008483-200305000-00016 · Cited by 2,937
Control of Synaptic Strength by Glial TNFα
Beattie, E. C., Stellwagen, D., Morishita, W., Bresnahan, J. C., Ha, B. K., Von Zastrow, M., Beattie, M. S., & Malenka, R. C. (2002) · Science · doi:10.1126/science.1067859 · Cited by 1,344
Advances in Male Contraception
Page, S. T., Amory, J. K., & Bremner, W. J. (2008) · Endocrine Reviews · doi:10.1210/er.2007-0041 · Cited by 1,138
Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins
Ray, S., Britschgi, M., Herbert, C., Takeda-Uchimura, Y., Boxer, A., Blennow, K., Friedman, L. F., Galasko, D. R., Jutel, M., Karydas, A., et al. (2007) · Nature Medicine · doi:10.1038/nm1653 · Cited by 1,048
Systemic infections and inflammation affect chronic neurodegeneration
Perry, V. H., Cunningham, C., & Holmes, C. (2007) · Nature Reviews Immunology · doi:10.1038/nri2015 · Cited by 1,027
Self-citation

Show all 42 references

Sorted by citations

Items 301–400 of 1,000

Brazilian Green Propolis Prevents Cognitive Decline into Mild Cognitive Impairment in Elderly People Living at High Altitude
Zhu, A., Wu, Z., Zhong, X., Ni, J., Li, Y., Meng, J., Du, C., Zhao, X. Y., Nakanishi, H., & Wu, S. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170630 · Cited by 70
The impact of age-related dysregulation of the angiotensin system on mitochondrial redox balance
Vajapey, R. S., Rini, D. A., Walston, J. D., & Abadir, P. M. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00439 · Cited by 70
Neuroprotective effects of glucose-dependent insulinotropic polypeptide in Alzheimer’s disease
Ji, C., Xue, G., Li, G., Li, D., & Hölscher, C. (2015) · Reviews in the Neurosciences · doi:10.1515/revneuro-2015-0021 · Cited by 70
Volunteering Is Associated with Lower Risk of Cognitive Impairment
Infurna, F. J., Okun, M. A., & Grimm, K. J. (2016) · Journal of the American Geriatrics Society · doi:10.1111/jgs.14398 · Cited by 75
“Inflammation, an indicator of poor immune functioning, is posited to be an antecedent of cognitive impairment.(46) The second direction for future research is to examine moderators of the association between volunteering and onset of cognitive impairment.”
Background
Systemic Inflammation Is Associated With Longitudinal Changes in Cognitive Performance Among Urban Adults
Beydoun, M. A., Dore, G. A., Canas, J. A., Liang, H., Beydoun, H. A., Evans, M. K., & Zonderman, A. B. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00313 · Cited by 67
Modifiable, Non-Modifiable, and Clinical Factors Associated with Progression of Alzheimer’s Disease
Loeffler, D. A. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201182 · Cited by 71
The importance of postoperative quality of recovery: influences, assessment, and clinical and prognostic implications
Bowyer, A., & Royse, C. F. (2015) · Canadian Journal of Anesthesia/Journal canadien d anesthésie · doi:10.1007/s12630-015-0508-7 · Cited by 67
Can Better Management of Periodontal Disease Delay the Onset and Progression of Alzheimer’s Disease?
Harding, A., Robinson, S. J., Crean, S., & Singhrao, S. K. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170046 · Cited by 69
Infection-Induced Systemic Inflammation Is a Potential Driver of Alzheimer's Disease Progression
Giridharan, V. V., Masud, F. N., Petronilho, F. C., Dal‐Pizzol, F., & Barichello, T. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00122 · Cited by 68
“An increased level of the systemic inflammatory marker TNF-α was demonstrated to be associated with an increase in cognitive decline in AD patients (Holmes et al., 2009).”
Background
Therapeutic implications of the prostaglandin pathway in Alzheimer's disease
Cudaback, E., Jorstad, N. L., Yang, Y. J., Montine, T. J., & Keene, C. D. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.12.014 · Cited by 68
Does Helicobacter pylori Infection Increase Incidence of Dementia? The Personnes Agées QUID Study
Baudron, C. R., Letenneur, L., Langlais, A., Buissonnière, A., Mégraud, F., Dartigues, J., Salles, N., & Study, F. T. P. A. Q. (2012) · Journal of the American Geriatrics Society · doi:10.1111/jgs.12065 · Cited by 66
Associations between pro‐inflammatory cytokines, learning, and memory in late‐life depression and healthy aging
Charlton, R. A., Lamar, M., Zhang, A., Ren, X., Ajilore, O., Pandey, G. N., & Kumar, A. (2017) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.4686 · Cited by 72
“Previous studies have suggested that a combination of current inflammatory markers and reported inflammatory events better predicts outcome than inflammatory markers alone (Holmes et al., 2009).”
BackgroundInfluential
Low-grade peripheral inflammation affects brain pathology in the AppNL-G-Fmouse model of Alzheimer’s disease
Xie, J., Gorlé, N., Vandendriessche, C., Imschoot, G. V., Wonterghem, E. V., Cauwenberghe, C. V., Parthoens, E., Hamme, E. V., Lippens, S., Hoecke, L. V., et al. (2021) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01253-z · Cited by 69
Association between Helicobacter pylori infection and dementia
Huang, W.-S., Yang, T.-Y., Shen, W., Lin, C., Lin, M., & Kao, C. (2014) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2013.11.018 · Cited by 65
“A recent report showed that systemic inflammation is associated with accelerated, delirium-independent cognitive decline in patients with AD [16].”
Background
Leptomeningeal Cells Transduce Peripheral Macrophages Inflammatory Signal to Microglia in Reponse to Porphyromonas gingivalis LPS
Liu, Y., Wu, Z., Zhang, X., Ni, J., Yu, W., Zhou, Y., & Nakanishi, H. (2013) · Mediators of Inflammation · doi:10.1155/2013/407562 · Cited by 66
“Therefore, it is reasonable to consider that the increased M1 polarization of macrophages during chronic periodontitis can be also a risk factor for AD, because the elevated levels of TNF-α and IL1-β are associated not only with the cognitive decline but also with the progression of AD [45–47].”
Background
Peripheral Inflammation and Insulin Resistance: Their Impact on Blood–Brain Barrier Integrity and Glia Activation in Alzheimer’s Disease
Ponce-Lopez, T. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26094209 · Cited by 75
“Several studies suggest that chronic peripheral inflammation may cause an increase in proinflammatory cytokines in the CNS by crossing the BBB and eliciting an inflammatory response in microglia, contributing to neuroinflammation and cognitive impairment in patients with or without AD [190,191].”
Perispinal etanercept: a new therapeutic paradigm in neurology
Tobinick, E. L. (2010) · Expert Review of Neurotherapeutics · doi:10.1586/ern.10.52 · Cited by 64
Inflammatory Markers in Mild Cognitive Impairment: A Meta-Analysis
Saleem, M., Herrmann, N., Swardfager, W., Eisen, R. B., & Lanctôt, K. L. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150042 · Cited by 64
The Role of Interleukin-18, Oxidative Stress and Metabolic Syndrome in Alzheimer’s Disease
Ojala, J. O., & Sutinen, E. M. (2017) · Journal of Clinical Medicine · doi:10.3390/jcm6050055 · Cited by 64
“Still, systemic inflammation can worsen symptoms in neurodegenerative diseases, including AD [17], and can also increase brain OS [18] as well as blood-brain barrier (BBB) permeability [19].”
Background
Cognitive impairment in patients with rheumatoid arthritis
Vitturi, B. K., Nascimento, B. A. C., Alves, B. R., de Campos, F. S. C., & Torigoe, D. Y. (2019) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2019.08.027 · Cited by 64
Choroid Plexus in Alzheimer’s Disease—The Current State of Knowledge
Gião, T., Teixeira, T., Almeida, M. R., & Cardoso, I. (2022) · Biomedicines · doi:10.3390/biomedicines10020224 · Cited by 64
“In fact, both acute and chronic inflammation are associated with the cognitive decline characteristic of the pathology [37].”
Background
High fat diet and its effects on cognitive health: alterations of neuronal and vascular components of brain
Sharma, S. (2021) · Physiology & Behavior · doi:10.1016/j.physbeh.2021.113528 · Cited by 70
Inflammation and Coagulation During Critical Illness and Long-Term Cognitive Impairment and Disability
Brummel, N. E., Hughes, C. G., Thompson, J. L., Jackson, J. C., Pandharipande, P. P., McNeil, J. B., Chandrasekhar, R., Orun, O. M., Ware, L. B., Bernard, G. R., et al. (2020) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201912-2449oc · Cited by 66
The Role of Butyrylcholinesterase and Iron in the Regulation of Cholinergic Network and Cognitive Dysfunction in Alzheimer’s Disease Pathogenesis
Jasiecki, J., Targońska, M., & Wasąg, B. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22042033 · Cited by 67
Metabolic Syndrome and the Cellular Phase of Alzheimer's Disease
Pugazhenthi, S. (2017) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2016.12.016 · Cited by 65
Relationships Between Ion Channels, Mitochondrial Functions and Inflammation in Human Aging
Strickland, M., Yacoubi‐Loueslati, B., Bouhaouala‐Zahar, B., Pender, S. L. F., & Larbi, A. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00158 · Cited by 64
Hyperactive Innate Immunity Causes Degeneration of Dopamine Neurons upon Altering Activity of Cdk5
Shukla, A. K., Spurrier, J. M., Kuzina, I., & Giniger, E. (2019) · Cell Reports · doi:10.1016/j.celrep.2018.12.025 · Cited by 62
“Neuroinflammation is an important component of many NDs, including Alzheimer disease (AD), frontotemporal dementia (FTD), Parkinson disease (PD), and others (Gjoneska et al., 2015; Heneka et al., 2014; Holmes et al., 2009; Richards et al., 2016; Zhang, 2015).”
Scavenger Receptor-A deficiency impairs immune response of microglia and astrocytes potentiating Alzheimer’s disease pathophysiology
Cornejo, F., Vruwink, M., Metz, C., Muñoz, P., Salgado, N., Poblete, J., Andrés, M. E., Eugenín, J., & von Bernhardi, R. (2018) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2017.12.007 · Cited by 59
The relationship between Helicobacter pylori infection and Alzheimer’s disease in Japan
Shiota, S., Murakami, K., Yoshiiwa, A., Yamamoto, K., Ohno, S., Kuroda, A., Mizukami, K., Hanada, K., Okimoto, T., Kodama, M., et al. (2011) · Journal of Neurology · doi:10.1007/s00415-011-5957-5 · Cited by 61
Periodontal Disease Associated with Higher Risk of Dementia: Population‐Based Cohort Study in Taiwan
Lee, Y., Hu, H., Huang, L., Chou, P., & Chu, D. (2017) · Journal of the American Geriatrics Society · doi:10.1111/jgs.14944 · Cited by 61
Neuroprotective Role of the Nrf2 Pathway in Subarachnoid Haemorrhage and Its Therapeutic Potential
Zolnourian, A. H., Galea, I., & Bulters, D. O. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/6218239 · Cited by 62
“Neuroinflammation has been shown to be associated with cognitive dysfunction in other disorders [79, 80] so this could be a putative mechanism underlying such deficits in SAH patients.”
Background
Alterations of Transcription of Genes Coding Anti-oxidative and Mitochondria-Related Proteins in Amyloid β Toxicity: Relevance to Alzheimer’s Disease
Cieślik, M., Czapski, G. A., Wójtowicz, S., Wieczorek, I., Wencel, P. L., Strosznajder, R. P., Jaber, V. R., Lukiw, W. J., & Strosznajder, J. B. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-01819-y · Cited by 61
Protection of Alzheimer’s disease progression by a human-origin probiotics cocktail
Prajapati, S. K., Wang, S., Mishra, S. P., Jain, S., & Yadav, H. (2025) · Scientific Reports · doi:10.1038/s41598-024-84780-8 · Cited by 64
Baseline C-Reactive Protein Levels and Life Prognosis in Parkinson Disease
Sawada, H., Oeda, T., Umemura, A., Tomita, S., Kohsaka, M., Park, K., Yamamoto, K., & Sugiyama, H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0134118 · Cited by 60
The impact of neuroimmune changes on development of amyloid pathology; relevance to A lzheimer's disease
Lynch, M. A. (2013) · Immunology · doi:10.1111/imm.12156 · Cited by 64
Impact of aging immune system on neurodegeneration and potential immunotherapies
Liang, Z., Zhao, Y., Ruan, L., Zhu, L., Jin, K., Zhuge, Q., Su, D., & Zhao, Y. L. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.07.006 · Cited by 64
“Clinical observation showed that acute systemic inflammationwith the high levels of TNF-a significantly increased in the rate of cognitive decline over a 6-month period (Holmes et al., 2009).”
Periodontal Disease and Periodontal Disease-Related Bacteria Involved in the Pathogenesis of Alzheimer’s Disease
Matsushita, K., Yamada-Furukawa, M., Kurosawa, M., & Shikama, Y. (2020) · Journal of Inflammation Research · doi:10.2147/jir.s255309 · Cited by 64
Presenilin 2 Is the Predominant γ-Secretase in Microglia and Modulates Cytokine Release
Jayadev, S., Case, A., Eastman, A. J., Nguyen, H., Pollak, J., Wiley, J. C., Möller, T., Morrison, R. S., & Garden, G. A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015743 · Cited by 60
“Elevated proinflammatory cytokine serum levels are associated with both the acquisition of neurodegeneration and progression of cognitive decline [27,28].”
Background
Adiponectin, leptin and IL-1 β in elderly diabetic patients with mild cognitive impairment
Górska-Ciebiada, M., Saryusz‐Wolska, M., Borkowska, A., Ciebiada, M., & Loba, J. M. (2015) · Metabolic Brain Disease · doi:10.1007/s11011-015-9739-0 · Cited by 56
“In other studies, increased levels of TNF-α and IL-1β were found in the cerebrospinal fluid and plasma in patients with Alzheimer’s disease (Holmes et al. 2009; Forlenza et al. 2009).”
Background
The Role of Microglia in Prion Diseases: A Paradigm of Functional Diversity
Obst, J., Simon, E., Mancuso, R., & Gómez‐Nicola, D. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00207 · Cited by 61
“Systemic infection and increased systemic inflammation have been associated to an enhanced cognitive decline in AD patients (Holmes et al., 2003, 2009, 2011), and systemic infections are associated with relapses in multiple sclerosis in patients (Buljevac et al., 2002).”
Background
Effects of kidney function, serum albumin and hemoglobin on dementia severity in the oldest old people with newly diagnosed Alzheimer’s disease in a residential aged care facility: a cross-sectional study
Wu, J.-J., Weng, S., Liang, C., Lin, C., Lan, T., Lin, S.-Y., & Lin, Y. (2020) · BMC Geriatrics · doi:10.1186/s12877-020-01789-0 · Cited by 58
“As inflammatory mechanisms are involved in the pathogenesis of dementia, including Alzheimer’s disease [36], low serum albumin levels may become a risk factor for cognitive decline in AD.”
Background
Alzheimer's disease and periodontitis - an elusive link
Gurav, A. N. (2014) · Revista da Associação Médica Brasileira · doi:10.1590/1806-9282.60.02.015 · Cited by 62
Inflammation and dementia: Using rheumatoid arthritis as a model to develop treatments?
Mason, A., Holmes, C., & Edwards, C. J. (2018) · Autoimmunity Reviews · doi:10.1016/j.autrev.2018.04.001 · Cited by 59
Self-citation
Molecular Signaling Mechanisms of Natural and Synthetic Retinoids for Inhibition of Pathogenesis in Alzheimer’s Disease
Chakrabarti, M., McDonald, A. J., Will Reed, J., Moss, M. A., Das, B. C., & Ray, S. K. (2016) · Journal of Alzheimer's Disease · doi:10.3233/jad-150450 · Cited by 57
Molecular imaging in Alzheimer's disease: new perspectives on biomarkers for early diagnosis and drug development
Nordberg, A. K. (2011) · Alzheimer s Research & Therapy · doi:10.1186/alzrt96 · Cited by 58
Genetics of Late‐Onset Alzheimer′s Disease: Update from the Alzgene Database and Analysis of Shared Pathways
Olgiati, P., Politis, A. M., Papadimitriou, G. N., Ronchi, D. D., & Serretti, A. (2011) · International Journal of Alzheimer s Disease · doi:10.4061/2011/832379 · Cited by 58
“Etanercept, a biological antagonist of TNFalpha, is under evaluation as a therapeutic agent for AD.”
Background
Neuroprotective effect of peptides extracted from walnut (Juglans Sigilata Dode) proteins on Aβ25-35-induced memory impairment in mice
Zou, J., Cai, P., Xiong, C., & Ruan, J. (2016) · Journal of Huazhong University of Science and Technology [Medical Sciences] · doi:10.1007/s11596-016-1536-4 · Cited by 58
Intricate role of sleep deprivation in modulating depression: focusing on BDNF, VEGF, serotonin, cortisol, and TNF-α
Vaseghi, S., Mostafavijabbari, A., Alizadeh, M.-S., Ghaffarzadegan, R., Kholghi, G., & Zarrindast, M. (2022) · Metabolic Brain Disease · doi:10.1007/s11011-022-01124-z · Cited by 59
Plasma Signaling Proteins in Persons at Genetic Risk for Alzheimer Disease
Ringman, J. M., Elashoff, D. A., Geschwind, D. H., Welsh, B. T., Gylys, K. H., Lee, C., Cummings, J. L., & Cole, G. M. (2012) · Archives of Neurology · doi:10.1001/archneurol.2012.277 · Cited by 58
Delirium Diagnostic and Classification Challenges in Palliative Care: Subsyndromal Delirium, Comorbid Delirium-Dementia, and Psychomotor Subtypes
Leonard, M. M., Agar, M. R., Spiller, J. A., Davis, B., MOHAMAD, M. R., Meagher, D. J., & Lawlor, P. G. (2014) · Journal of Pain and Symptom Management · doi:10.1016/j.jpainsymman.2014.03.012 · Cited by 56
Amelioration of LPS-Induced Inflammation Response in Microglia by AMPK Activation
Chen, C.-C., Lin, J., Cheng, Y.-F., Kuo, C., Huang, C.-F., Kao, S., Liang, Y.-J., Cheng, C., & Chen, H.-M. (2014) · BioMed Research International · doi:10.1155/2014/692061 · Cited by 56
Neutrophil-Derived Microvesicle Induced Dysfunction of Brain Microvascular Endothelial Cells In Vitro
Ajikumar, A., Long, M. B., Heath, P. R., Wharton, S. B., Ince, P. G., Ridger, V. C., & Simpson, J. E. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20205227 · Cited by 59
Biomarkers of delirium risk in older adults: a systematic review and meta-analysis
Lozano-Vicario, L., García‐Hermoso, A., Cedeño‐Veloz, B. A., Fernández‐Irigoyen, J., Santamaría, E., Romero‐Ortuño, R., Zambom-Ferraresi, F., de Asteasu, M. L. S., Muñoz-Vázquez, Á. J., Izquierdo, M., et al. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1174644 · Cited by 57
Systemic Inflammation in Asthma: What Are the Risks and Impacts Outside the Airway?
Tattersall, M. C., Jarjour, N. N., & Busse, P. J. (2024) · The Journal of Allergy and Clinical Immunology In Practice · doi:10.1016/j.jaip.2024.02.004 · Cited by 58
Male Sex Hormones and Systemic Inflammation in Alzheimer Disease
Butchart, J., Birch, B. R., Bassily, R., Wolfe, L., & Holmes, C. (2012) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e318258cd63 · Cited by 55
Self-citation
Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice
Souchet, B., Audrain, M., Billard, J. M., Dairou, J., Fol, R. R., Orefice, N. S., Tada, S., Gu, Y., Dufayet‐Chaffaud, G., Limanton, E., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0678-6 · Cited by 60
Selective memory and behavioral alterations after ambient ultrafine particulate matter exposure in aged 3xTgAD Alzheimer’s disease mice
Jew, K., Herr, D., Wong, C., Kennell, A., Morris‐Schaffer, K., Oberdörster, G., O’Banion, M. K., Cory‐Slechta, D. A., & Elder, A. C. P. (2019) · Particle and Fibre Toxicology · doi:10.1186/s12989-019-0323-3 · Cited by 55
Proteomics as a reliable approach for discovery of blood-based Alzheimer’s disease biomarkers: A systematic review and meta-analysis
Rehiman, S. H., Lim, S. M., Neoh, C. F., Majeed, A. B. A., Chin, A., Tan, M. P., Kamaruzzaman, S. B., & Ramasamy, K. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101066 · Cited by 54
Enduring Changes in Neuronal Function upon Systemic Inflammation Are NLRP3 Inflammasome Dependent
Beyer, M. M. S., Lonnemann, N., Remus, A., Latz, E., Heneka, M. T., & Korte, M. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.0200-20.2020 · Cited by 55
“Increasing evidence suggests a connection between inflammatory conditions in the brain/body and Alzheimer’s disease (AD; Holmes et al., 2009; Heneka et al., 2015).”
Background
Dopamine activates NF-κB and primes the NLRP3 inflammasome in primary human macrophages
Nolan, R. A., Reeb, K. L., Rong, Y., Matt, S. M., Johnson, H. S., Runner, K., & Gaskill, P. J. (2019) · Brain Behavior & Immunity - Health · doi:10.1016/j.bbih.2019.100030 · Cited by 54
Induced Pluripotent Stem Cell-Derived Neural Precursors Improve Memory, Synaptic and Pathological Abnormalities in a Mouse Model of Alzheimer’s Disease
Armijo, E., Edwards, G. A., Flores, A., Vera, J. R., Shahnawaz, M., Moda, F., González, C., Sanhueza, M., & Soto, C. A. (2021) · Cells · doi:10.3390/cells10071802 · Cited by 57
Plasma neopterin level as a marker of peripheral immune activation in amnestic mild cognitive impairment and Alzheimer's disease
Parker, D., Mielke, M. M., Yu, Q., Rosenberg, P. B., Jain, A., Lyketsos, C. G., Fedarko, N. S., & Oh, E. S. (2012) · International Journal of Geriatric Psychiatry · doi:10.1002/gps.3802 · Cited by 54
“Studies have shown that systemic inflammation is associated with cognitive decline in older adults (Yaffe et al., 2003), and increased risk of the development (Tan et al., 2007) or progression of AD (Blasko et al., 2007, Holmes et al., 2009).”
Background
The independent role of inflammation in physical frailty among older adults with mild cognitive impairment and mild-to-moderate Alzheimer's disease
Tay, L. B. G., Lim, W. S., Chan, M. Y., Ye, R. J., & Chong, M. S. (2015) · The journal of nutrition health & aging · doi:10.1007/s12603-015-0617-6 · Cited by 57
“…with AD pathology on post-mortem examination suggests a common etiopathogenesis for physical frailty and AD (13), a hypothesis that is further supported by evidence of chronic systemic inflammation and hormonal deficits (14-18), as well as common vascular risk factors (19, 20) in both conditions.”
The Neutrophil to Lymphocyte Ratio Is Associated With the Risk of Subsequent Dementia in the Framingham Heart Study
Ramos-Cejudo, J., Johnson, A. D., Beiser, A., Seshadri, S., Salinas, J., Berger, J. S., Fillmore, N. R., Do, N., Zheng, C., Kovbasyuk, Z., et al. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.773984 · Cited by 49
“In addition, clinical studies have indicated that the inflammatory status influences the rate of disease progression in patients with AD (Holmes et al., 2009; Cunningham and Hennessy, 2015).”
Background
Liver X receptors: Emerging therapeutic targets for Alzheimer's disease
Sodhi, R. K., & Singh, N. (2013) · Pharmacological Research · doi:10.1016/j.phrs.2013.03.008 · Cited by 61
Association Between Periodontitis and Cognitive Impairment in Adults: A Systematic Review
Nascimento, P. C., Castro, M. M. L., Magno, M. B., Almeida, A. P. C. P. S. C., Fagundes, N. C. F., Maia, L. C., & Lima, R. R. (2019) · Frontiers in Neurology · doi:10.3389/fneur.2019.00323 · Cited by 58
Cytokines and inflammatory biomarkers and their association with post-operative delirium: a meta-analysis and systematic review
Mosharaf, M. P., Alam, K., Gow, J., & Mahumud, R. A. (2025) · Scientific Reports · doi:10.1038/s41598-024-82992-6 · Cited by 61
Preventive effects of dexmedetomidine on the development of cognitive dysfunction following systemic inflammation in aged rats
Yamanaka, D., Kawano, T., Nishigaki, A., Aoyama, B., Tateiwa, H., Shigematsu-Locatelli, M., Locatelli, F. M., & Yokoyama, M. (2016) · Journal of Anesthesia · doi:10.1007/s00540-016-2264-4 · Cited by 55
“Another prospective study further showed that acute SI events among elderly subjects with Alzheimer’s disease were associated with a twofold increase in the rate of cognitive decline over time [5].”
Background
Peripheral inflammatory markers indicate microstructural damage within periventricular white matter hyperintensities in Alzheimer's disease: A preliminary report
Swardfager, W., Yu, D., Ramirez, J., Cogo‐Moreira, H., Szilagyi, G. M., Holmes, M. F., Scott, C. J. M., Scola, G., Chan, P. C., Chen, J., et al. (2017) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1016/j.dadm.2016.12.011 · Cited by 53
“Several studies have suggested longitudinal relationships between peripheral inflammatory markers and cognitive decline in AD [2], but how these observations relate precisely to changes in brain tissue is not well understood.”
Background
Synaptic plasticity modulation by circulating peptides and metaplasticity: Involvement in Alzheimer’s disease
Peineau, S., Rabiant, K., Pierrefiche, O., & Potier, B. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.01.018 · Cited by 56
Rapamycin treatment for Alzheimer’s disease and related dementias: a pilot phase 1 clinical trial
Gonzales, M. M., Garbarino, V. R., Kautz, T. F., Song, X., Lopez‐Cruzan, M., Linehan, L. A., Skike, C. E. V., de Erausquin, G. A., Galván, V., Orr, M. E., et al. (2025) · Communications Medicine · doi:10.1038/s43856-025-00904-9 · Cited by 56
Anticholinergics boost the pathological process of neurodegeneration with increased inflammation in a tauopathy mouse model
Yoshiyama, Y., Kojima, A., Itoh, K., Uchiyama, T., & Arai, K. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.08.017 · Cited by 52
Potential Future Neuroprotective Therapies for Neurodegenerative Disorders and Stroke
Tarawneh, R. M., & Galvin, J. E. (2010) · Clinics in Geriatric Medicine · doi:10.1016/j.cger.2009.12.003 · Cited by 54
Chronic peripheral inflammation: a possible contributor to neurodegenerative diseases
Süβ, P., Lana, A. J., & Schlachetzki, J. C. M. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.306060 · Cited by 55
Peripheral inflammatory biomarkers predict the deposition and progression of amyloid-β in cognitively unimpaired older adults
Oberlin, L. E., Erickson, K. I., Mackey, R. H., Klunk, W. E., Aizenstein, H. J., Lopresti, B. J., Kuller, L. H., López, O. L., & Snitz, B. E. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.03.015 · Cited by 56
Cytokine signaling convergence regulates the microglial state transition in Alzheimer’s disease
Lau, S., Fu, A. K. Y., & Ip, N. Y. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03810-0 · Cited by 55
Neuroinflammatory and behavioural changes in the Atp7B mutant mouse model of Wilson’s disease
Terwel, D., Löschmann, Y., Schmidt, H., Schöler, H. R., Cantz, T., & Heneka, M. T. (2011) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2011.07278.x · Cited by 52
“For instance, Holmes et al. (2009) observed that both acute and chronic systemic inflammation is associated with an increase in cognitive decline in Alzheimer’s disease.”
Background
Inflammation, Cognition, and White Matter in Older Adults: An Examination by Race
Boots, E. A., Castellanos, K. J., Zhan, L., Barnes, L. L., Tussing-Humphreys, L. M., Deoni, S., & Lamar, M. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.553998 · Cited by 50
“In fact, prior studies in older White adults show direct associations between elevated peripheral inflammation and dementia (Holmes et al., 2009; Swardfager et al., 2010) as well as alterations in cerebral white matter and cognition (Wersching et al.”
Background
Non-Steroidal Anti-Inflammatory Drugs and Cognitive Function: Are Prostaglandins at the Heart of Cognitive Impairment in Dementia and Delirium ?
Cunningham, C. M., & Skelly, D. (2011) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-011-9312-5 · Cited by 51
“Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.”
BackgroundSelf-citation
G protein–coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation‐induced sensitization to excitotoxic neurodegeneration
Degos, V., Peineau, S., Nijboer, C. H. A., Kaindl, A. M., Sigaut, S., Favrais, G., Plaisant, F., Teissier, N., Gouadon, E., Lombet, A., et al. (2013) · Annals of Neurology · doi:10.1002/ana.23868 · Cited by 51
Selective Acetyl- and Butyrylcholinesterase Inhibitors Reduce Amyloid-β Ex Vivo Activation of Peripheral Chemo-cytokines From Alzheimer’s Disease Subjects: Exploring the Cholinergic Anti-inflammatory Pathway
Reale, M., Nicola, M. D., Velluto, L., D’Angelo, C., Costantini, E., Lahiri, D. K., Kamal, M. A., Yu, Q.-S., & Greig, N. H. (2014) · Current Alzheimer Research · doi:10.2174/1567205010666131212113218 · Cited by 51
“disorders, and particularly in AD [12-14].”
Systemic Inflammation and Multimodal Biomarkers in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease
Magalhães, T. N. C., Weiler, M., Teixeira, C. V. L., Hayata, T., Moraes, A. S., Boldrini, V. D. O., dos Santos, L. M., de Campos, B. M., de Rezende, T. J. R., Joaquim, H. P. G., et al. (2017) · Molecular Neurobiology · doi:10.1007/s12035-017-0795-9 · Cited by 51
“In a cognitive context, AD patients who present acute systemic infections with elevations in TNF-α serum have accelerated rates of cognitive decline [18, 61].”
Background
Similarity and Differences in Inflammation-Related Characteristics of the Peripheral Immune System of Patients with Parkinson’s and Alzheimer’s Diseases
Boyko, A., Troyanova, N. I., Kovalenko, E. I., & Sapozhnikov, A. M. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122633 · Cited by 54
“It has also been demonstrated that proinflammatory mediators induced during activation of the innate and adaptive immunity can penetrate through the blood–brain barrier and affect the CNS, contributing to an exacerbation of neurodegeneration by activation of primed microglial cells [30,31].”
Background
A differentiating neural stem cell-derived astrocytic population mitigates the inflammatory effects of TNF-α and IL-6 in an iPSC-based blood-brain barrier model
Mantle, J. L., & Lee, K. H. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.07.030 · Cited by 52
Bacopa monnieri prevents colchicine-induced dementia by anti-inflammatory action
Saini, N., Singh, D., & Sandhir, R. (2019) · Metabolic Brain Disease · doi:10.1007/s11011-018-0332-1 · Cited by 51
Increased Inflammatory Response in Cytomegalovirus Seropositive Patients with Alzheimer’s Disease
Westman, G., Berglund, D., Widén, J., Ingelsson, M., Korsgren, O., Lannfelt, L., Sehlin, D., Lidehäll, A. K., & Eriksson, B. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096779 · Cited by 50
“In addition, offspring with a parental history of AD present with a more proinflammatory cytokine profile than those without [4] and patients with AD seem to deteriorate in cognitive capacity when challenged with inflammatory events [5].”
Background
Meningeal and choroid plexus cells—Novel drug targets for CNS disorders
Dragunow, M. (2013) · Brain Research · doi:10.1016/j.brainres.2013.01.013 · Cited by 51
Macrophage Migration Inhibitory Factor is Associated with Biomarkers of Alzheimer’s Disease Pathology and Predicts Cognitive Decline in Mild Cognitive Impairment and Mild Dementia
Oikonomidi, A., Tautvydaitė, D., Gholam‐Rezaee, M., Henry, H., Bacher, M., & Popp, J. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170335 · Cited by 51
Longitudinal relationship of severe periodontitis with cognitive decline in older Japanese
Iwasaki, M., Yoshihara, A., Kimura, Y., Sato, M., Wada, T., Sakamoto, R., Ishimoto, Y., Fukutomi, E., Chen, W., Imai, H., et al. (2016) · Journal of Periodontal Research · doi:10.1111/jre.12348 · Cited by 49
Periodontitis Is Associated with Cognitive Impairment in Elderly Koreans: Results from the Yangpyeong Cohort Study
Shin, H., Shin, M., Ahn, Y., Choi, B. Y., Nam, J., & Kim, H. (2016) · Journal of the American Geriatrics Society · doi:10.1111/jgs.13781 · Cited by 49
“The current study confirmed results of previous studies that periodontitis is associated with cognitive impairment.(12,22) To the best of the knowledge of the authors of the current study, the results are the first evidence of the association between periodontitis and cognitive impairment in elderly Koreans.”
Result
Plasma Markers of Inflammation Linked to Clinical Progression and Decline During Preclinical AD
Gross, A. L., Walker, K. A., Moghekar, A. R., Pettigrew, C., Soldan, A., Albert, M. S., & Walston, J. D. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00229 · Cited by 49
Behavioral and neuropsychiatric disorders in Alzheimer's disease
Cortés, N., Andrade, V., & Maccioni, R. B. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-180005 · Cited by 57
Effect of Continuous Ingestion of Bifidobacteria and Dietary Fiber on Improvement in Cognitive Function: A Randomized, Double-Blind, Placebo-Controlled Trial
Azuma, N., Mawatari, T., Saito, Y., Tsukamoto, M., Sampei, M., & Iwama, Y. (2023) · Nutrients · doi:10.3390/nu15194175 · Cited by 54
Post-Marketing Assessment of Neuropsychiatric Adverse Events in Influenza Patients Treated with Oseltamivir: An Updated Review
Toovey, S., Prinssen, E. P. M., Rayner, C. R., Thakrar, B. T., Dutkowski, R. T., Koerner, A., Chu, T., Sirzen‐Zelenskaya, A., Britschgi, M., Bansod, S., et al. (2012) · Advances in Therapy · doi:10.1007/s12325-012-0050-8 · Cited by 48
“The upregulation of systemic immune pathways, whether by viral infection or other stimulus, is known to significantly affect CNS function in Alzheimer’s disease and multiple sclerosis [112, 113], and cytokines may play an important role in the pathogenesis of depression [114] and sleep disorders [115].”
Microglia in Alzheimer's Disease: a Key Player in the Transition Between Homeostasis and Pathogenesis
McFarland, K. N., & Chakrabarty, P. (2022) · Neurotherapeutics · doi:10.1007/s13311-021-01179-3 · Cited by 48
DAT and TH expression marks human Parkinson’s disease in peripheral immune cells
Gopinath, A., Mackie, P. M., Hashimi, B., Buchanan, A. M., Smith, A. R., Bouchard, R. S., Shaw, G., Badov, M., Saadatpour, L., Gittis, A. H., et al. (2022) · npj Parkinson s Disease · doi:10.1038/s41531-022-00333-8 · Cited by 47
Allergy influences the inflammatory status of the brain and enhances tau‐phosphorylation
Sarlus, H., Höglund, C. O., Karshikoff, B., Wang, X., Lekander, M., Schultzberg, M., & Oprica, M. (2012) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2012.01556.x · Cited by 50
Inflammation and clinical presentation in neurodegenerative disease: a volatile relationship
Bettcher, B. M., & Kramer, J. H. (2012) · Neurocase · doi:10.1080/13554794.2011.654227 · Cited by 49
“Furthermore, baseline levels of inflammatory markers (eg, TNF-α) have also been shown to predict an increased rate of cognitive deterioration in AD, as indexed by the ADAS-COG score ( Holmes et al, 2009 ).”
Neutrophil-to-lymphocyte ratio predicts diagnosis and prognosis of idiopathic sudden sensorineural hearing loss
Chen, L., Zhang, G., Zhang, Z., Wang, Y., Hu, L., & Wu, J. (2018) · Medicine · doi:10.1097/md.0000000000012492 · Cited by 47
Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APPswe/PS1ΔE9 Transgenic Mice
Myhre, C. L., Thygesen, C., Villadsen, B., Vollerup, J., Ilkjær, L., Krohn, K. T., Grebing, M., Zhao, S., Khan, A. M., Dissing‐Olesen, L., et al. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00308 · Cited by 45
“, 2014), and increased serum levels of TNF in AD patients (Perry et al., 2001; Holmes et al., 2009; Swardfager et al., 2010), might potentially impair hippocampal neurogenesis and/or neuroblast survival and differentiation.”
Background

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Systemic inflammation and disease progression in Alzheimer disease

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks