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Inflammation as a central mechanism in Alzheimer's disease
Open accessAbstract
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 as summarized by the recent reviews.9,253,412”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [9]
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“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“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]
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“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“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]
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“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]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
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“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]
The cited source says what the claim attributes to it.
In the citing paper
“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
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Research works printed but not linked: 3
- Alzheimer's Impact Movement, 2017, Alzheimer's Disease Caregivers Factsheet
- 10.1186/1750-1326-9-20 · DOI · Paper page
- 10.1186/s13024-017-0216-6 · DOI · Paper page
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“63 Accordingly, we here assess TWS influence on AD in this context.”
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“In addition, sustained microglial activation may induce a reduction in microglia efficiency for binding and phagocytosing Aβ.(41) However, a biological link between brain Aβ pathology and cerebral microvascular damage cannot be ruled out.”
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“The sustained activation of microglia cells has been shown to exacerbate both amyloid and tau pathology and may serve as a link in the pathogenesis of AD (110, 111).”
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Mechanistic insights into the role of herpes simplex virus 1 in Alzheimer’s disease
Feng, S., Liu, Y., Zhou, Y., Shu, Z., Cheng, Z., Brenner, C., & Feng, P. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1245904 · Cited by 36
Ekundayo, B. E., Obafemi, T. O., Afolabi, B. A., Adewale, O. B., Onasanya, A., Osukoya, O. A., Falode, J. A., Akintayo, C. O., & Adu, I. A. (2022) · Pharmacological Research - Modern Chinese Medicine · doi:10.1016/j.prmcm.2022.100193 · Cited by 43
Kılıç, B., Bardakkaya, M., Sağkan, R. I., Aksakal, F., Shakila, S., & Doğruer, D. S. (2022) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2022.106322 · Cited by 39
Effects of small molecules on neurogenesis: Neuronal proliferation and differentiation
Jastrzębski, M. K., Wójcik, P., Stępnicki, P., & Kaczor, A. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.10.007 · Cited by 40
Targeting CaN/NFAT in Alzheimer’s brain degeneration
Mackiewicz, J., Lisek, M., & Boczek, T. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1281882 · Cited by 41
Lorenzo, D. D. (2024) · ChemMedChem · doi:10.1002/cmdc.202400180 · Cited by 46
Hebbian and Homeostatic Synaptic Plasticity—Do Alterations of One Reflect Enhancement of the Other?
Galanis, C., & Vlachos, A. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00050 · Cited by 43
“Along this line of evidence, a role for microglia in Aβ-mediated alterations in complex brain function has been suggested (Kitazawa et al., 2004; Hansen et al., 2018; Kinney et al., 2018; Hemonnot et al., 2019).”
BackgroundPKR kinase directly regulates tau expression and Alzheimer's disease‐related tau phosphorylation
Reimer, L., Betzer, C., Kofoed, R. H., Volbracht, C., Fog, K., Kurhade, C., Nilsson, E., Överby, A. K., & Jensen, P. H. (2020) · Brain Pathology · doi:10.1111/bpa.12883 · Cited by 39
“This hypothesis could potentially explain the underlying pathological pathways leading to CTE and dementing in war veterans and retired athletes from physical contact sports such as American football and boxing (18, 21, 45) and the substantial role of inflammation in the progression of AD (33).”
BackgroundThe inhibition of LSD1 via sequestration contributes to tau-mediated neurodegeneration
Engstrom, A., Walker, A. C., Moudgal, R. A., Myrick, D. A., Kyle, S. M., Bai, Y., Rowley, M. J., & Katz, D. J. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2013552117 · Cited by 39
Spatial memory deficiency early in 6xTg Alzheimer’s disease mouse model
Kang, S., Kim, J., & Chang, K.-A. (2021) · Scientific Reports · doi:10.1038/s41598-020-79344-5 · Cited by 39
Bretland, K. A., Lin, L., Bretland, K. M., Smith, M. A., Fleming, S. M., & Crish, S. D. (2021) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12711 · Cited by 43
Elastin-Derived Peptides in the Central Nervous System: Friend or Foe
Szychowski, K. A., Skóra, B., & Wójtowicz, A. K. (2021) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-021-01140-0 · Cited by 40
Zhang, B., Lian, W., Zhao, J., Wang, Z., Liu, A., & Du, G. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6521146 · Cited by 42
“and synaptic loss are the common results of oxidative stress and neuroinflammatory damage [46], and also the direct cause of learning and cognitive impairment caused by Dgalactose.”
BackgroundTargeting Systemic Innate Immune Cells as a Therapeutic Avenue for Alzheimer Disease
Pons, V., & Rivest, S. (2022) · Pharmacological Reviews · doi:10.1124/pharmrev.121.000400 · Cited by 41
“The last decade, inflammation was thought to be the main cause of AD, but neuroinflammation is now seen as a consequence of AD rather than a cause (Kinney et al., 2018).”
BackgroundKlotho an Autophagy Stimulator as a Potential Therapeutic Target for Alzheimer’s Disease: A Review
Fung, T., Iyaswamy, A., Sreenivasmurthy, S. G., Krishnamoorthi, S., Guan, X.-J., Zhu, Z., Su, C.-F., Liu, J., Kan, Y., Zhang, Y., et al. (2022) · Biomedicines · doi:10.3390/biomedicines10030705 · Cited by 43
“IL-1β regulates the production of APP and further increases the Aβ burden and plaque deposition, eventually leading to the development of AD [100].”
BackgroundSingh, V., Kaur, K., Kaur, S., Shri, R., Singh, T. G., & Singh, M. (2022) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2022.115438 · Cited by 40
A closer look at the mycobiome in Alzheimer’s disease: Fungal species, pathogenesis and transmission
Phuna, Z. X., & Madhavan, P. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15599 · Cited by 41
“paramount in promoting virulence via several mechanisms: (1) invasion of hyphae into epithelial cell (Kumamoto & Vinces, 2005), (2) breaching and damaging of endothelial cells by hyphae (Jong et al., 2001; Kumamoto & Vinces, 2005) and (3) lysis of both macrophages and neutrophils due to hyphal growth after phagocytosi…”
CNS Redox Homeostasis and Dysfunction in Neurodegenerative Diseases
Goldsteins, G., Hakosalo, V., Jaronen, M., Keuters, M. H., Lehtonen, Š., & Koıstınaho, J. (2022) · Antioxidants · doi:10.3390/antiox11020405 · Cited by 42
Sex Hormones, Sleep, and Memory: Interrelationships Across the Adult Female Lifespan
Harrington, Y. A., Parisi, J. M., Duan, D., Rojo‐Wissar, D. M., Holingue, C., & Spira, A. P. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.800278 · Cited by 42
Neurodegenerative Microbially-Shaped Diseases: Oxidative Stress Meets Neuroinflammation
Silva, D. F., Empadinhas, N., Cardoso, S. M., & Esteves, A. R. (2022) · Antioxidants · doi:10.3390/antiox11112141 · Cited by 44
“According to the inflammation hypothesis for AD, inflammation, and specially neuroinflammation, play a pivotal role in progression of neuropathological hallmarks observed in AD [57].”
BackgroundAssociations between saliva and plasma cytokines in cognitively normal, older adults
Parkin, G. M., Kim, S., Mikhail, A. P., Malhas, R., McMillan, L. C., Hollearn, M. K., Granger, D. A., Mapstone, M. E., Yassa, M. A., & Thomas, E. A. (2022) · Aging Clinical and Experimental Research · doi:10.1007/s40520-022-02292-9 · Cited by 42
Xiong, Y., Huang, Y., Li, L., Liu, Y., Liu, L., Wang, L., Tong, L., Wang, F., & Fan, B. (2023) · Molecules · doi:10.3390/molecules28031223 · Cited by 39
Pan, X., Yun, J., Coban‐Akdemir, Z., Jiang, X., Wu, E., Huang, J. H., Sahni, N., & Yi, S. S. (2023) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2023.02.004 · Cited by 36
The intricate role of CCL5/CCR5 axis in Alzheimer disease
Ma, W., Liu, A., Wu, X., Gao, L., Chen, J., Wu, H., Liu, M., Fan, Y., Li, P., Yang, J., et al. (2023) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlad071 · Cited by 41
Miyazawa, K., Fukunaga, H., Tatewaki, Y., Takano, Y., Yamamoto, S., Mutoh, T., & Taki, Y. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165783 · Cited by 37
Franke, T. N., Irwin, C., Bayer, T. A., Brenner, W., Beindorff, N., Bouter, C., & Bouter, Y. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.00529 · Cited by 37
Huang, X., Zhao, X., Li, B., Cai, Y., Zhang, S., Yu, F., & Wan, Q. (2021) · Experimental Gerontology · doi:10.1016/j.exger.2021.111424 · Cited by 39
Wirt, R. A., Crew, L. A., Ortiz, A. A., McNeela, A. M., Flores, E., Kinney, J. W., & Hyman, J. M. (2021) · Communications Biology · doi:10.1038/s42003-021-02558-4 · Cited by 41
Self-citationBannai, D., Adhan, I. K., Katz, R., Kim, L. A., Keshavan, M. S., Miller, J. B., & Lizano, P. L. (2021) · Schizophrenia Bulletin · doi:10.1093/schbul/sbab111 · Cited by 39
Oral microbiome and serological analyses on association of Alzheimer's disease and periodontitis
Fu, K., Chiu, M., Wara‐aswapati, N., Yang, C., Chang, L., Guo, Y. L., Ni, Y., & Chen, Y. (2022) · Oral Diseases · doi:10.1111/odi.14348 · Cited by 38
Blivet, G., Relaño-Ginés, A., Bodnar‐Wachtel, M., & Touchon, J. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220467 · Cited by 37
Huang, J., Wu, F., Cao, W., Chen, Y., Yao, Q., Cen, P., Wang, J., Lu, H., Zhang, X. H., Zhou, R., et al. (2024) · Biomaterials · doi:10.1016/j.biomaterials.2024.123042 · Cited by 41
Salani, F., Sterbini, V., Sacchinelli, E., Garramone, M., & Bossù, P. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01768 · Cited by 37
“Aβ plaques are surrounded by activated glial cells releasing inflammatory mediators, hence the sustained neuroinflammatory response has emerged as a third core pathological feature of AD (37), with an acknowledged role in disease pathogenesis and evolution (38, 39).”
BackgroundBeneficial effects of curtailing immune susceptibility in an Alzheimer’s disease model
Benedetto, G. D., Burgaletto, C., Carta, A. R., Saccone, S., Lempereur, L., Mulas, G., Loreto, C. D., Bernardini, R., & Cantarella, G. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1554-9 · Cited by 38
Moore, A. M., Mahoney, E. R., Dumitrescu, L. C., Jager, P. L. D., Koran, M. E. I., Petyuk, V., Robinson, R. A. S., Ruderfer, D. M., Cox, N. J., Schneider, J. A., et al. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.10.021 · Cited by 38
Ano, Y., Ohya, R., Takaichi, Y., Washinuma, T., Uchida, K., Takashima, A., & Nakayama, H. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-190997 · Cited by 37
“Studies have indicated that inflammatory-type M1 microglia promote synapse loss and memory impairment, thereby exacerbating the pathologies in AD [4, 8]; accordingly, recent studies have targeted activated microglia as a therapeutic target in AD [24].”
BackgroundXu, A., He, F., Zhang, X., Li, X., Ran, Y., Wei, C., Chou, C. J., Zhang, R., & Wu, J. (2020) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2020.103721 · Cited by 39
Biomarkers: Our Path Towards a Cure for Alzheimer Disease
Tarawneh, R. M. (2020) · Biomarker Insights · doi:10.1177/1177271920976367 · Cited by 42
Dong, H., Qian, Y., Bhuiyan, P., Wang, Y., & Sha, H.-H. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.310608 · Cited by 39
“Hyperactivation of hypothalamic MCs can stimulate the HPA axis through histamine and CRH, which regulate hypothalamic function and can also increase CRH/CRH-R mRNA expression in the hypothalamus (Bugajski et al., 1995; Kjaer et al., 1998; Ayyadurai et al., 2017).”
BackgroundMetabolic Syndrome: Is It Time to Add the Central Nervous System?
Rojas, M., Chávez-Castillo, M., Pírela, D., Parra, H., Nava, M., Chacín, M., Angarita, L., Áñez, R., Salazar, J. J., Ortíz, R., et al. (2021) · Nutrients · doi:10.3390/nu13072254 · Cited by 40
“An associated hypothesis is that, along with neurofibrillary tangles and amyloid-beta plaques, inflammation has a critical role in the pathophysiology of the disease [43].”
BackgroundAlzheimer’s Disease: From Pathogenesis to Mesenchymal Stem Cell Therapy – Bridging the Missing Link
Hu, J., & Wang, X. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.811852 · Cited by 42
Nguyen, H. D., Jo, W. H., Hoang, N. H. M., & Kim, M. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.108736 · Cited by 38
The potential impact of Covid-19 on CNS and psychiatric sequels
Dehghani, A., Zokaei, E., Kahani, S. M., Alavinejad, E., Dehghani, M., Meftahi, G. H., & Afarinesh, M. R. (2022) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2022.103097 · Cited by 38
“between immune system activity and memory decline (Kinney et al., 2018).”
Clark, J., Kayed, R., Kayed, R., Abate, G., Kinnon, P., & Kinnon, P. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.835288 · Cited by 38
“Inflammation An inflammatory environment has been linked to, specifically an immune infiltrate localized to amyloid plaques within the AD brain to AD pathology (Kinney et al., 2018).”
BackgroundInfluentialA new generation of AD biomarkers: 2019 to 2021
Hawksworth, J. I., Fernández, E., & Gevaert, K. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101654 · Cited by 34
Implications of Microorganisms in Alzheimer’s Disease
Yadav, P., Lee, Y., Panday, H., Kant, S., Bajwa, N., Parashar, R., Jha, S. K., Jha, N. K., Nand, P., Lee, S., et al. (2022) · Current Issues in Molecular Biology · doi:10.3390/cimb44100314 · Cited by 37
“Inflammation in the brain is thought to be brought about by two independent mechanisms: first, a loss of BBB in the systemic circulation, and second, agents that affect certain neuronal pathways [68,69].”
BackgroundGut Microbiota and Immune System Dynamics in Parkinson’s and Alzheimer’s Diseases
Kuštrimović, N. Z., Balkhi, S., Bilato, G., & Mortara, L. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252212164 · Cited by 39
“These pathological features contribute to neuronal damage, oxidative stress, synaptic dysfunction, and neuroinflammation, ultimately leading to synaptic and neuronal loss that ultimately affects memory, reasoning, and other cognitive functions and results in brain atrophy [161–163] (Figure 4).”
Qian, W., Liu, D., Liu, J., Liu, M., Ji, Q., Zhang, B., Yang, Z., Cheng, Y., & Zhou, S. (2024) · Small · doi:10.1002/smll.202408581 · Cited by 38
Metadata
- 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)
- 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
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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