Inflammation as a central mechanism in Alzheimer's disease

Kinney, Jefferson W.; Bemiller, Shane M.; Murtishaw, Andrew S.; Leisgang, Amanda M.; Salazar, Arnold M.; Lamb, Bruce T.

doi:10.1016/j.trci.2018.06.014

Cited by 2,253Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Inflammation as a central mechanism in Alzheimer's disease

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Kinney, Jefferson W., Bemiller, Shane M., Murtishaw, Andrew S., Leisgang, Amanda M., Salazar, Arnold M., Lamb, Bruce T.·2018·Alzheimer's & Dementia: Translational Research & Clinical Interventions

DOI 10.1016/j.trci.2018.06.014PMC PMC6214864

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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive decline and the presence of two core pathologies, amyloid β plaques and neurofibrillary tangles. Over the last decade, the presence of a sustained immune response in the brain has emerged as a third core pathology in AD. The sustained activation of the brain's resident macrophages (microglia) and other immune cells has been demonstrated to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of the disorder. In the following review, we provide an overview of inflammation in AD and a detailed coverage of a number of microglia‐related signaling mechanisms that have been implicated in AD. Additional information on microglia signaling and a number of cytokines in AD are also reviewed. We also review the potential connection of risk factors for AD and how they may be related to inflammatory mechanisms.

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Numerous cytokines and chemokines have been shown to contribute to the pathogenesis of neurodegenerative diseases.
“Numerous cytokines and chemokines have been shown to contribute to the pathogenesis of neurodegenerative diseases as summarized by the recent reviews.9,253,412”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [9]
The Microglia section says pro-inflammatory cytokines contribute to neurodegeneration, and the CX3CR1 and AD section discusses a chemokine pathway relevant to Alzheimer’s pathology. The review focuses on Alzheimer’s disease and describes that chemokine pathway as complex; it does not establish that numerous chemokines contribute to the pathogenesis of neurodegenerative diseases generally. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
The immune response activates glia and induces secretion of pro-inflammatory cytokines, which can drive further aggregation of Aβ by affecting the capacity of microglia and astrocytes for phagocytosis and degradation.
“This immune response in turn activates glia and induces the secretion of pro-inflammatory cytokines, which can drive further aggregation of Aβ by affecting the capacity of microglia and astrocytes for phagocytosis and degradation [26].”
From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [26]
The 'Inflammation in AD > Microglia' section (page unavailable) says prolonged immune activation sustains pro-inflammatory cytokine signaling while reducing microglial Aβ phagocytosis and degrading-enzyme activity, leading to Aβ accumulation. It does not establish that cytokines cause this loss of clearance capacity or describe a corresponding loss of phagocytosis and degradation by astrocytes. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Chronic microglial inflammation has been observed in the brains of AD patients at various disease stages, and pro-inflammatory cytokines such as IL-1β, IL-2, IL-6, and tumor necrosis factor-α have been shown to be upregulated in AD.
“Chronic microglial inflammation has been observed in the brains of AD patients at various disease stages, and pro-inflammatory cytokines such as IL-1β, IL-2, IL-6, and tumor necrosis factor-α have been shown to be upregulated in AD [35].”
From Cerebrospinal fluid levels of the neurotrophic factor neuroleukin are increased in early Alzheimer’s disease, but not in cerebral amyloid angiopathy (2021) · cites this paper as [35]
The Overview describes chronic neuroinflammation in AD as involving activated microglia. The Specific cytokine signaling in AD section reports elevated IL-1β, IL-6, and TNF-α in AD patients, including IL-1β in both MCI and AD. Our copy does not establish that IL-2 is upregulated in AD, so the full cytokine list is not supported. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Aβ levels are generally well-correlated with immune activation indicated by microgliosis and astrocytosis.
“Aβ levels are generally well-correlated with immune activation indicated by microgliosis and astrocytosis [3].”
From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [3]
The Microglia section (page unavailable) links Aβ to microglial activation and describes reactive microgliosis alongside Aβ accumulation. The Specific cytokine signaling in AD section (page unavailable) places reactive gliosis around Aβ plaques, but the copy does not establish that Aβ levels are generally well-correlated with both microgliosis and astrocytosis. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Innate immune system activation, in particular microglia, is considered a contributing factor to Alzheimer's disease pathogenesis rather than a consequence of pathology.
“Currently, the innate immune system activation, in particular microglia, is considered a contributing factor to AD pathogenesis rather than a consequence of pathology 2 .”
From ABI3 deletion in TgCRND8 mice is associated with reduced amyloid plaque pathology and altered glial response (2023) · cites this paper as [2]
The Microglia section says prolonged microglial activation exacerbates AD pathology, supporting its role as a contributor. But the Inflammation in AD section says neuroinflammation is typically thought to result from other AD pathologies or risk factors, rather than being causal on its own. The source therefore does not support the claim’s ‘rather than a consequence’ distinction. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measured

Neuroinflammatory responses are considered a major driving factor in patients with neurodegeneration and Alzheimer's disease pathology, which starts early in the course of the disease, prior to the formation of Aβ plaques in the brain.
“Theses neuroinflammatory responses are considered a major driving factor in patients with neurodegeneration and Alzheimer’s disease pathology, which starts early in the course of the disease, prior to the formation of Aβ plaques in the brain73.”
From Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk (2022) · cites this paper as [73]
The Overview and Inflammation in AD sections describe sustained neuroinflammation as a central feature of neurodegenerative disorders and a contributor to AD pathology. They do not establish that it begins before Aβ plaques form; the Microglia section instead describes Aβ as a hypothesized primary driver of microglial activation. The paper copy provides no page numbers for these passages. (LLM, conf=0.86)
Experimental — accuracy not yet measured
In the comparison between B6 and 5xFAD mice, the concentrations of IL-1β and TNFα were increased, and those of IL-10 and IL-5 were decreased.
“In the comparison between B6 and 5xFAD mice, the concentrations of two proinflammatory cytokines, interleukin-1 β (IL-1B), tumor necrosis factor-alpha (TNFα ), were increased Figure 3G), and those of two other cytokines, IL-10, IL-5, were decreased (Figure 3H), consistent with previous findings 30 .”
From Genetic variants of phospholipase C-γ2 alter the phenotype and function of microglia and confer differential risk for Alzheimer’s disease (2023) · cites this paper as [30]
The review’s “Specific cytokine signaling in AD” section reports elevated IL-1β and TNF-α in people with AD, which supports the direction of those two findings only at a different population level. It does not report a B6-versus-5xFAD comparison or decreased IL-5; the same section describes IL-10 as upregulated in patients with AD, rather than supporting the claimed decrease in mice. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Prolonged microglial activation may be detrimental, leading to a self-perpetuating cycle involving production of neurotoxic pro-inflammatory cytokines, damaging neurons, inducing more recruitment of microglia, further increasing their activation and release of pro-inflammatory cytokines.
“Prolonged microglial activation may be detrimental, since it eventually leads to a self-perpetuating cycle involving the production of neurotoxic pro-inflammatory cytokines, damaging neurons, inducing more recruitment of microglia, further increasing their activation and release of pro-inflammatory cytokines [35].”
From Cerebrospinal fluid levels of the neurotrophic factor neuroleukin are increased in early Alzheimer’s disease, but not in cerebral amyloid angiopathy (2021) · cites this paper as [35]
Neuroinflammation is linked to neurodegeneration and neuronal loss, which are features associated with amyloid plaque formation.
“Neuroinflammation is also linked to neurodegeneration and neuronal loss, which are features that coincidently are associated with amyloid plaque formation (DeTure and Dickson, 2019; Kinney et al., 2018; Sung et al., 2020).”
From Arbovirus infection increases the risk for the development of neurodegenerative disease pathology in the murine model (2024) · cites this paper as Kinney et al., 2018
Due to dysregulation of the GABAergic mechanism in AD, the inhibitory role of GABA on activated microglia is lost, which further contributes to the release of pro-inflammatory cytokines.
“Due to the dysregulation of GABAergic mechanism in AD, the inhibitory role of GABA on activated microglia is also lost which further contributes to the release of pro-inflammatory cytokines [17].”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [17]
The chronic, sustained inflammatory response in the brain is considered the third core pathological feature of AD.
“The chronic, sustained inflammatory response in the brain is considered the third core pathological feature of AD.”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [84]
Chronic neuroinflammation is caused by persistent activation of glial cells and excessive release of cytotoxic molecules, adversely affects brain function, and is a major cofactor in the pathogenesis of many neurodegenerative disorders including AD.
“This chronic neuroinflammation is caused by persistent activation of glial cells and excessive release of cytotoxic molecules, which adversely affects brain function and is a major cofactor in the pathogenesis of many neurodegenerative disorders, including AD [84].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [84]
Chronic neuroinflammation provides a link between the other two core AD pathologies, Aβ plaques and NFTs.
“It provides a link between the other two core pathologies, Aβ plaques and NFTs [84].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [84]
Continuous activation of brain immune cells such as microglia leads to release and production of proinflammatory cytokines, which aids tau and amyloid-beta pathologies and leads to loss of neurons.
“Continuous activation of the brain’s immune cells, such as microglia, leads to the release and production of various proinflammatory cytokines, which aids tau and Aβ pathologies and leads to the loss of neurons [24].”
From The Multifaceted Role of Neuroprotective Plants in Alzheimer’s Disease Treatment (2022) · cites this paper as [24]

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[150]Ulrich J.D. Finn M.B. Wang Y. Shen A. Mahan T.E. Jiang H. Altered microglial response to Abeta plaques in APPPS1-21 mice heterozygous for TREM2 Mol Neurodegener 9 2014 20 24893973 PMC4049806
[156]Bemiller S.M. McCray T.J. Allan K. Formica S.V. Xu G. Wilson G. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy Mol Neurodegener 12 2017 74 29037207 PMC5644120

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Authors: Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T.
Affiliations: University of Nevada, Las Vegas (US)
Indiana University Indianapolis (US)
Department of Psychology University of Nevada Las Vegas Las Vegas NV USA
Corresponding author: Kinney, Jefferson W.
ORCID: Lamb, Bruce T.
Venue: Alzheimer's & Dementia: Translational Research & Clinical Interventions
Publisher: Wiley
Published: 2018-01
Volume: 4
Issue: 1
Pages: 575-590
ISSN: 2352-8737 (ISSN-L)
DOI: 10.1016/j.trci.2018.06.014
PMC: PMC6214864
OpenAlex: W2889787710
Cited by: 2,253
References: 283
Citations by year: 2026: 187 · 2025: 395 · 2024: 401 · 2023: 353 · 2022: 326 · 2021: 286 · 2020: 226 · 2019: 76 · 2018: 1
FWCI: 13.95
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by-nc-nd
creativecommons.org/licenses/by-nc-nd/4.0/ (vor, 247 d)
Locations: Alzheimer s & Dementia Translational Research & Clinical Interventions (publishedVersion, cc-by-nc-nd)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Digital Scholarship - UNLV (University of Nevada Reno) (submittedVersion, cc-by-nd)
Digital Scholarship - UNLV (University of Nevada Reno) (submittedVersion, cc-by-nc-nd)
IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
Funders: National Institutes of Health (P20GM109025)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords: Alzheimer's disease, neuroinflammation, microglia, amyloid plaques, neurofibrillary tangles, tau pathology, cytokines, risk factors, neurodegeneration

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Inflammation as a central mechanism in Alzheimer's disease

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