Cited by 501Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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Intrathecal inflammation precedes development of Alzheimer's disease

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Tarkowski, E·2003·Journal of Neurology, Neurosurgery & Psychiatry

DOI 10.1136/jnnp.74.9.1200PMC PMC1738668

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Abstract

OBJECTIVES: To analyse the cerebrospinal fluid (CSF) values of the proinflammatory cytokines, interleukin 1beta (IL1beta), tumour necrosis factor alpha (TNFalpha), GM-CSF, of the anti-inflammatory cytokine TGFbeta, of tau protein, a marker for neurodegeneration, and of beta amyloid (Abeta), a protein involved in the formation of senile plaques, in prospectively followed up patients with mild cognitive impairment (MCI). METHODS: Analyses of CSF levels of TNFalpha, IL1beta, GM-CSF, TGFbeta, betaa, and tau protein were performed using ELISA in 56 patients with MCI who were followed up prospectively and in 25 age matched, healthy controls. RESULTS: Patients with MCI displayed significantly higher levels of TNFalpha and tau protein and significantly lower levels of TGFbeta and Abeta compared with the healthy controls. After nine months of follow up, 25 patients still displayed MCI while the remaining 31 patients had progressed to Alzheimer's disease (AD). Only MCI patients who progressed to AD at follow up, showed significantly higher CSF levels of TNFalpha than controls. In addition, reduced CSF-Abeta42 levels were only found in MCI patients that progressed to AD, further supporting the notion that disturbed metabolism of Abeta is an early finding in AD. CONCLUSIONS: These results demonstrate increased production of the proinflammatory cytokine, TNFalpha and decreased production of the anti-inflammatory cytokine TGFbeta in patients with MCI at risk to develop AD, suggesting a propensity towards inflammation in this patient group and indicating that CNS inflammation is a early hallmark in the pathogenesis of AD.

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Navarro‐Sempere, A., Garcı́a, M., Rodrigues, A., Garcia, P., Camarinho, R., & Segovia, Y. (2020) · Journal of Toxicology and Environmental Health · doi:10.1080/15287394.2020.1850381 · Cited by 7
Signaling pathways mediating a selective induction of nitric oxide synthase II by tumor necrosis factor alpha in nerve growth factor-responsive cells
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“For example, inflammatory involvement in AD pathogenesis has been proposed partly based on observations of increased levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF α ) and interleukin-1 beta (IL-1 β ) in cerebrospinal fluid and brain cortex of AD patients [26,27].”
Late-long-term potentiation magnitude, but not Aβ levels and amyloid pathology, is associated with behavioral performance in a rat knock-in model of Alzheimer disease
Yesiltepe, M., Yin, T., Tambini, M. D., Breuillaud, L., Zehntner, S. P., & D’Adamio, L. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.1040576 · Cited by 6
“A pathogenic role for neuroinflammation in AD has emerged (Akiyama et al., 2000; Tarkowski et al., 2003).”
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Unraveling APOE4: The dual role in CNS and peripheral inflammation in Alzheimer's disease
Li, X., Li, Z., Chen, H., Guo, H., Ge, Y., Dong, F., Zhang, F., & Zhang, F. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.115199 · Cited by 7
Association between Body Iron Status and Cognitive Task Performance in a Nationally Representative Sample of Older Adults
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“Those aged 60 to 69 are in the early stage of cognitive decline, when the role of inflammatory reaction is more significant [37], resulting in an abnormal increase of serum ferritin.”
Electrophysiological insights into Alzheimer's disease: A review of human and animal studies
Calvin, K., McNeela, A. M., Osse, A. M. L., Bhasin, G., Ridenour, M., Kinney, J. W., & Hyman, J. M. (2024) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2024.105987 · Cited by 8
Putative Involvement of Cytokine Modulation in the Development of Perioperative Neurocognitive Disorders
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“CSF cytokines have been shown to be increased in depression,34 schizophrenia35 and neurodegenerative disorders such as AD.25 Some cytokines have pro-inflammatory effects, such as TNF-α, IL-1β, IL-6 and IL-8, and others, such as IL-4, IL-10 and IL-13, have anti-inflammatory effects.36 In most tissues, cytokines are rel…”
Background
Computational Analysis of Pathogenetic Pathways in Alzheimer’s Disease and Prediction of Potential Therapeutic Drugs
Petralia, M. C., Mangano, K., Quattropani, M. C. A., Lenzo, V., Nicoletti, F., & Fagone, P. (2022) · Brain Sciences · doi:10.3390/brainsci12070827 · Cited by 6
“Neuroinflammation is a feature of AD brain pathology [36], and the role of the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), in the pathogenesis AD has long been presumed [37,38].”
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Microglial Drivers of Alzheimer's Disease Pathology: An Evolution of Diverse Participating States
Kuhn, M. K., & Proctor, E. A. (2024) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.26723 · Cited by 5
The Role of PGE2 in Age-related Diseases
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Trans Fatty Acids, does Exist Safety Dosage?
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“There is growing evidence that lipid metabolism, oxidative stress and inflammatory mechanisms may also participate in the pathogenesis of AD [18].”
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Relationship between cytokine levels in the cerebrospinal fluid and 11C‐Pittsburgh compound B retention in patients with mild cognitive impairment
Abe, Y., Kimura, N., Takahashi, R., Gotou, M., Mizukami, K., Uchida, H., & Matsubara, E. (2017) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/ggi.12991 · Cited by 5
JNK3 Overexpression in the Entorhinal Cortex Impacts on the Hippocampus and Induces Cognitive Deficiencies and Tau Misfolding
Ardanaz, C. G., Ezkurdia, A., Bejarano, A., Echarte, B., Smerdou, C., Martišová, E., Martínez-Valbuena, I., Luquín, M. R., Ramírez, M. J., & Solas, M. (2023) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.3c00092 · Cited by 5
Evaluating Fatty Acid Amide Hydrolase as a Suitable Target for Sleep Promotion in a Transgenic TauP301S Mouse Model of Neurodegeneration
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“Therefore, to test the hypothesis that FAAH KO”
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Role of astrocytes in Alzheimer's disease pathogenesis and the impact of exercise-induced remodeling
Shao, J., Deng, Q., Feng, S., Wu, C., Liu, X., & Yang, L. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.150418 · Cited by 5
Drug-induced dementia: a real-world pharmacovigilance study using the FDA Adverse Event Reporting System database
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“…in many organ systems, including the brain, and it is significantly elevated in the cerebrospinal fluid of patients with dementia, affecting disease progression, 51 and it has also been shown that targeting TNF-α improves cognition in middle-aged and older adults and may treat or prevent dementia.”
Effects of a Mindfulness-Based Intervention on Circulating Cytokine Levels in Individuals with Amnestic Mild Cognitive Impairment: A Pilot Study
Morin-Alain, V., Larouche, E., Chouinard, A.-M., Audet, M.-C., Goulet, S., Rousseau, L.-S., & Hudon, C. (2020) · OBM Integrative and Complementary Medicine · doi:10.21926/obm.icm.2002022 · Cited by 3
“Indeed, as mentioned earlier, higher circulating levels of TNF-α, as compared to healthy controls, were associated with a higher risk of progression from MCI to AD [86].”
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Design and characterization of a novel dimeric blood–brain barrier penetrating TNFα inhibitor
Suárez, V. M., Macaya, L., Contreras, M. A., Parra, N. C., Maura, R., González, A., Toledo, J. R., & Sánchez, O. (2021) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.26173 · Cited by 6
Can MRI T1 be used to detect early changes in 5xFAD Alzheimer’s mouse brain?
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“In addition, there is now good evidence for neuroinflammation in the brain of AD patients [4, 5].”
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Editorial: cytokine inhibition for treatment of Alzheimer's disease.
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Pathogenesis of Alzheimer’s disease: Involvement of the Choroid PlexusPreprint
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Correction: Age-Dependent Neuroplasticity Mechanisms in Alzheimer Tg2576 Mice Following Modulation of Brain Amyloid-β Levels
Lilja, A. M., Röjdner, J., Mustafiz, T., ThomÃ©, C. M., Storelli, E., Gonzalez, D., Lithner, C. U., Greig, N. H., Nordberg, A. K., & Marutle, A. (2013) · PLoS ONE · doi:10.1371/annotation/79c850e6-4494-4533-b68d-ef4eb72cd65a · Cited by 5
The Therapeutic Potential of Dalbergia pinnata (Lour.) Prain Essential Oil in Alzheimer’s Disease: EEG Signal Analysis In Vivo, SH-SY5Y Cell Model In Vitro, and Network Pharmacology
Qin, S., Fang, J., He, X., Yu, G., Yi, F., & Zhu, G. (2024) · Biology · doi:10.3390/biology13070544 · Cited by 4
“Therefore, patients with mild cognitive impairment accompanied by high levels of the pro-inflammatory cytokine TNF-α and low levels of the anti-inflammatory cytokine TGF-β in their cerebrospinal fluid (CSF) are considered to have a high tendency for AD development [21].”
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Exploring the pathogenesis and key genes associated of acute myocardial infarction complicated with Alzheimer’s disease
Liu, C., Pan, F., Sun, Z., Chen, Z., & Wang, J. (2024) · Scientific Reports · doi:10.1038/s41598-024-52094-4 · Cited by 4
“Previous studies had revealed that inflammatory processes have been detected in the brains of people with AD 34 .”
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Association of Autoimmune Disorders and Disease-modifying Antirheumatic Drugs: (DMARDs) with the Risk of Alzheimer’s and/or Dementia: A Population Study Using Medicare Beneficiary Data
Ding, Q., Lamberts, J. T., Konieczny, A., Bringedahl, T. B., & Garcia, K. Y. T. (2023) · Current Alzheimer Research · doi:10.2174/0115672050289966240110041616 · Cited by 4
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Rommy von Bernhardi, M., & Eugenín, J. L. (2024) · Advances in neurobiology · doi:10.1007/978-3-031-55529-9_21 · Cited by 4
Construction of AAV-rat-IL4 and Evaluation of its Modulating Effect on Aβ (1-42)-Induced Proinflammatory Cytokines in Primary Microglia and the B92 Cell Line by Quantitative PCR Assay
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“(1-42)-induced proinflammatory cytokines in a primary microglia cell culture and the B92 rat microglia continuous cell line, using”
BackgroundMethodInfluential
Gene Expression Profile in Different Age Groups and Its Association with Cognitive Function in Healthy Malay Adults in Malaysia
Sani, N. F. A., Hamzah, A. I. Z. A., Bakar, Z. H. A., Yusof, Y. A. M., Makpol, S., Ngah, W. Z. W., & Damanhuri, H. A. (2021) · Cells · doi:10.3390/cells10071611 · Cited by 4
Deciphering the focal role of endostatin in Alzheimer’s disease
Kaur, D., Behl, T., Chigurupati, S., Sehgal, A., Singh, S., Sharma, N., Badavath, V. N., Vargas-De-La-Cruz, C. B., Bhatia, S., Al‐Harrasi, A., et al. (2021) · Environmental Science and Pollution Research · doi:10.1007/s11356-021-16567-7 · Cited by 4
“Modern analysis has shifted focus to cytokine-mediated neuroinflammation as a prime donor in the advancement of Alzheimer’s disease, and pieces of evidence show that inflammation advances pathological activities that catalyze AD (Tarkowski et al. 2003; Akiyama et al. 2000).”
Background
New potential biomarkers of Alzheimer's disease: markers of endothelial dysfunction and neuroinflammation.
Minochkin, A. K., Lobzin, V. Y., Николаевна, С. Н., Попов, О. С., Апалько, С. В., & Sherbak, S. G. (2022) · Neurology neuropsychiatry Psychosomatics · doi:10.14412/2074-2711-2022-2-35-42 · Cited by 5
The role of immunity and neuroinflammation in genetic predisposition and pathogenesis of Alzheimer’s disease
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“Studies on the progression of mild cognitive impairment to Alzheimer’s dementia have shown that increased levels of proinflammatory cytokines such as TNF-α and decreased levels of the anti-inflammatory cytokine TGFβ are associated with the conversion to dementia [61].”
Perispinal Etanercept for Traumatic Brain Injury
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Mitochondria at the Base of Neuronal Innate Immunity in Alzheimer’s and Parkinson’s Diseases
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Alzheimer’s disease-specific cytokine secretion suppresses neuronal mitochondrial metabolismPreprint
Kuhn, M. K., Fleeman, R. M., Beidler, L. M., Snyder, A. M., Chan, D. C., & Proctor, E. A. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.07.536014 · Cited by 4
Cerebrospinal fluid levels of tumour necrosis factor-α and its receptors are not associated with disease progression in Alzheimer’s disease
Aljuhani, M. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1547185 · Cited by 4
“Although CSF studies on the TNF family are limited, the present findings of non-significant changes in TNF-α are consistent with previous studies (Tarkowski et al., 2003; Llano et al., 2012; Swardfager et al., 2010).”
Meningeal macrophages alleviate social memory defects in an early Alzheimer’s disease model
Ding, S., Chen, S., Jin, Y., Li, Y., Wang, Y., Wang, Y., Zhang, S., Pang, Y., Wang, Z., Feng, W., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03372-8 · Cited by 3
ADAM proteases in cytokine biology: Modulators of immune signaling, inflammation and cancer
Khattab, H., Solujic, J., & Saad, M. I. (2026) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2026.120137 · Cited by 4
Brain Delivery of Antibody-Derived Biologicals for Alzheimer’s Disease: An Updated Narrative Review
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Alzheimer’s neuroinflammation: A crosstalk between immune checkpoint PD1-PDL1 and ApoE-Heparin interactions?
Patil, S. P., DiFlumeri, J., Wellington, J., Fattakhova, E., & Oravic, M. (2022) · Medical Hypotheses · doi:10.1016/j.mehy.2022.110865 · Cited by 3
The potential protective role of peripheral immunophenotypes in Alzheimer’s disease: a Mendelian randomization study
Zuo, C., Hu, Z., Fan, Y., Hao, X., Li, M.-J., Shi, J.-J., Guo, M.-N., Ma, D., Liang, Y., Liang, Y.-Y., et al. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1403077 · Cited by 4
“Research indicates that reduced production of anti-inﬂammatory TGF-β heightens the risk of developing AD in individuals with mild cognitive impairment (Tarkowski, 2003).”
Background

Authors: Tarkowski, E.
Affiliations: University of Gothenburg (SE)
Corresponding author: Tarkowski, E
Venue: Journal of Neurology, Neurosurgery & Psychiatry
Publisher: BMJ
Published: 2003-09-01
Volume: 74
Issue: 9
Pages: 1200-1205
ISSN: 0022-3050 (ISSN-L)
DOI: 10.1136/jnnp.74.9.1200
PMC: PMC1738668
OpenAlex: W2071728536
Cited by: 501
References: 53
Citations by year: 2026: 16 · 2025: 17 · 2024: 45 · 2023: 28 · 2022: 43 · 2021: 51 · 2020: 23 · 2019: 30 · 2018: 32 · 2017: 23 · 2016: 18 · 2015: 16 · 2014: 14 · 2013: 13 · 2012: 18
FWCI: 6.52
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Neurology Neurosurgery & Psychiatry (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Rune och Ulla Amlövs Stiftelse för Neurologisk och Reumatologisk Forskning
Hjärt-Lungfonden
Göteborgs Läkaresällskap
Svenska Läkaresällskapet
Stiftelsen Konung Gustaf V:s 80-årsfond
Medical Research Council
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: Alzheimer's disease, mild cognitive impairment, cerebrospinal fluid biomarkers, intrathecal inflammation, inflammatory cytokines, TNF-α, IL-1β, GM-CSF, TGF-beta, tau protein, amyloid-beta, amyloid metabolism, neuroinflammation, disease progression
MeSH terms: Aged, Aged, 80 and over, Alzheimer Disease, Central Nervous System, Cognition Disorders, Female, Humans, Inflammation, Interleukin-1, Male, Middle Aged, Prospective Studies, Risk Factors, Tumor Necrosis Factor-alpha, Granulocyte-Macrophage Colony-Stimulating Factor, Amyloid beta-Peptides, tau Proteins, Plaque, Amyloid

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Intrathecal inflammation precedes development of Alzheimer's disease

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