Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?
Abstract
Alzheimer disease (AD) is the most common form of neurodegenerative disease, estimated to contribute 60-70% of all cases of dementia worldwide. According to the prevailing amyloid cascade hypothesis, amyloid-β (Aβ) deposition in the brain is the initiating event in AD, although evidence is accumulating that this hypothesis is insufficient to explain many aspects of AD pathogenesis. The discovery of increased levels of inflammatory markers in patients with AD and the identification of AD risk genes associated with innate immune functions suggest that neuroinflammation has a prominent role in the pathogenesis of AD. In this Review, we discuss the interrelationships between neuroinflammation and amyloid and tau pathologies as well as the effect of neuroinflammation on the disease trajectory in AD. We specifically focus on microglia as major players in neuroinflammation and discuss the spatial and temporal variations in microglial phenotypes that are observed under different conditions. We also consider how these cells could be modulated as a therapeutic strategy for AD.
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The beneficial effects of A11 might stem from a reduction in PU.1 activity below a threshold that otherwise causes microglia to acquire a detrimental and hyperinflammatory phenotype or that helps undo unresolved microglial activation.
“The beneficial effects of A11 might stem from a reduction in PU.1 activity below a threshold that otherwise causes the microglia to acquire a detrimental and hyperinflammatory phenotype (Crotti et al., 2014; Gjoneska et al., 2015) or that helps the undoing of unresolved microglial activation (Leng and Edison, 2021).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Leng and Edison, 2021
Growing body of evidence supports the involvement of the neuroimmune system, mast cells, and microglia in AD onset and progression.
“The effort to find an innovative non-amyloid-based compound acting on neuroinflammation could be another treatment option since the growing body of evidence supports the involvement of the neuroimmune system, mast cells (MCs), and microglia in AD onset and progression [125,126].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [126]
Several other markers of TSPO are being developed and tested in dementia such as 11C-PBR28 and 11C-DAA1106.
“Considering the limitations of PK-PET, several other markers of TSPO are being developed and tested in dementia such as 11C-PBR28, 11C-DAA1106 (for review see [225]).”
From The use of neuroimaging techniques in the early and differential diagnosis of dementia (2023) · cites this paper as [225]
Persistent neuroinflammation and oxidative stress are factors in Alzheimer's disease progression.
“persistent neuroinflammation and oxidative stress are widely recognized as factors in the progression of AD11”
From Small-molecule PCSK9 inhibition enhances BBB amyloid-β clearance and suppresses microglial inflammation in Alzheimer’s disease models (2026) · cites this paper as [11]
As Aβ accumulates, microglia become persistently activated, causing prolonged inflammatory signaling and increased neurotoxic cytokine production that aggravate synaptic and neuronal injury.
“As Aβ accumulates, microglia become persistently activated, resulting in prolonged inflammatory signaling and increased production of neurotoxic cytokines that aggravate synaptic and neuronal injury11.”
From Small-molecule PCSK9 inhibition enhances BBB amyloid-β clearance and suppresses microglial inflammation in Alzheimer’s disease models (2026) · cites this paper as [11]
Neuroinflammation represents another critical driver of Alzheimer's disease progression.
“Neuroinflammation represents another critical driver of AD progression11.”
From Small-molecule PCSK9 inhibition enhances BBB amyloid-β clearance and suppresses microglial inflammation in Alzheimer’s disease models (2026) · cites this paper as [11]
Gliosis is another pathological hallmark of AD, emerging at very early stages of the disease.
“Gliosis is another pathological hallmark of AD, emerging at very early stages of the disease. 50 , 51”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [50]
Amyloid plaque formation is typically accompanied by gliosis.
“Although the causal link between Aβ accumulation and gliosis remains unclear, amyloid plaque formation is typically accompanied by gliosis.”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [50]
Excessive inflammatory activation of brain-resident immune cells in response to AD-related neuropathology accelerates neurodegeneration.
“The excessive inflammatory activation of brain-resident immune cells in response to AD-related neuropathology is well studied and known to accelerate neurodegeneration (7, 8).”
From Understanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems (2025) · cites this paper as [8]
Microglia are important in engulfing and processing of Aβ.
“Recent advances have unveiled the importance of microglia in engulfing and processing of Aβ5.”
From Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease (2024) · cites this paper as [5]
Sensitization with IL-1α + TNF-α + C1q recapitulates microglial activation and is reported to enhance GFAP protein levels and astrocyte neurotoxicity.
“This sensitization intends to recapitulate that caused by microglial activation, a current condition in AD [70,71], reported to enhance GFAP protein levels and astrocyte neurotoxicity [44].”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [71]
Microglial activation is a current condition in AD.
“a current condition in AD [70,71]”
From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [71]
In the early epoch, donors had sparse Aβ plaques (albeit increasing in size) and pTau+ tangle-bearing neurons, accompanied by early increases in inflammatory or reactive microglial and astrocytic states and associated gene expression changes in relevant inflammatory and plaque-induced genes.
“In the early epoch, donors had sparse Aβ plaques (albeit increasing in size) and pTau+ tangle-bearing neurons, accompanied by early increases in inflammatory or reactive microglial7 and astrocytic states69 and associated gene expression changes in relevant inflammatory85 and plaque-induced genes (Fig. 8b).”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [85]
A significant trigger for astrocyte reactivity is neuroinflammation, involving pro-inflammatory molecules like cytokines and chemokines.
“A significant trigger for astrocyte reactivity is neuroinflammation, involving pro-inflammatory molecules like cytokines and chemokines (11–14).”
From Varicose projection astrocytes: Conserved reactive cells in brain pathology (2026) · cites this paper as [11]
Microglia are the resident macrophages of the central nervous system that exert protective function by phagocytosing and clearing pathological protein aggregates.
“Microglia are the resident macrophages of the central nervous system that exert protective function by phagocytosing and clearing pathological protein aggregates. 8”
From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [8]
Neuroinflammation and microglial activation are consistent features across neurodegenerative diseases, including AD, PD, HD, FTD, and ALS.
“Indeed, neuroinflammation and microglial activation are consistent features across neurodegenerative diseases, including AD,126–128 PD,86,129 HD,130,131 FTD,91,132 and ALS.89,133–135”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [126]
Activation of inflammatory processes and immune responses are commonly observed in AD brain tissues.
“In addition, activation of inflammatory processes and immune responses are commonly observed in AD brain tissues [5].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [5]
AD patients and mouse models have elevated levels of inflammatory markers, and several AD risk genes associated with innate immune function have been identified, suggesting that neuroinflammation plays a critical role in AD pathogenesis.
“AD patients and mouse models have elevated levels of inflammatory markers, and several AD risk genes associated with innate immune function have been identified, suggesting that neuroinflammation plays a critical role in AD pathogenesis.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [457]
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“Abnormal microglia activation is one of the typical pathological features in AD patients [11,34].”
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“This sensitization intends to recapitulate that caused by microglial activation, a current condition in AD [70,71], reported to enhance GFAP protein levels and astrocyte neurotoxicity [44].”
BackgroundAducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations
Cadiz, M. P., Gibson, K. A., Todd, K. T., Nascari, D. G., Massa, N., Lilley, M. T., Olney, K. C., Al-Amin, M. M., Jiang, H., Holtzman, D. M., et al. (2024) · Journal of Experimental Medicine · doi:10.1084/jem.20231363 · Cited by 55 · see citing works
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“…long-standing therapeutic challenges—particularly the limited efficacy of conventional treatments and the formidable barrier posed by the BBB. 14 53 Nanocarrier systems, endowed with excellent biocompatibility, engineering versatility, and superior BBB penetration capabilities, provide…”
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Mechanistic Insights for Drug Repurposing and the Design of Hybrid Drugs for Alzheimer’s Disease
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“Recent advances have unveiled the importance of microglia in engulfing and processing of Aβ 5 .”
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Lysosomal Functions in Glia Associated with Neurodegeneration
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Lipid metabolism transcriptomics of murine microglia in Alzheimer’s disease and neuroinflammation
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C/EBPβ/AEP Signaling Drives Alzheimer’s Disease Pathogenesis
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Evidence for immune system alterations in peripheral biological fluids in Parkinson’s disease
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A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation
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Nanotechnology in the diagnostic and therapy for Alzheimer's disease
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Versatile nanomaterials for Alzheimer’s disease: Pathogenesis inspired disease-modifying therapy
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The effect of Abi3 locus deletion on the progression of Alzheimer’s disease-related pathologies
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“While earlier studies considered gliosis just as a secondary response to Ab accumulation in AD, recent studies have demonstrated that gliosis starts at very early stages of the disease and may play an important role during disease progression (6, 34).”
BackgroundResultDuan, J., Lv, A., Guo, Z., Liu, Q., Tian, C., Yang, Y., Bi, J., Yu, X., Peng, G., Luo, B., et al. (2024) · Journal of Neuroinflammation · doi:10.1186/s12974-024-03243-z · Cited by 22 · see citing works
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Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain
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“The excessive inflammatory activation of brain-resident immune cells in response to AD-related neuro-pathology is well studied and known to accelerate neurodegeneration ( 7 , 8 ).”
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Varicose projection astrocytes: Conserved reactive cells in brain pathology
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“50,51 Although the causal link between A β accumulation and gliosis remains unclear, amyloid plaque formation is typically accompanied by gliosis.”
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“Neuroinflammation represents another critical driver of AD progression 11 .”
AXL-mediate GEF-H1 phosphorylation was involved in microglia synapse phagocytosis in 5xFAD mice
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- Authors
- Leng, F., & Edison, P.
- Affiliations
- Hammersmith Hospital (GB)
- Corresponding author
- Edison, Paul
- Venue
- Nature Reviews Neurology
- Published
- 2020-12-14
- Volume
- 17
- Issue
- 3
- Pages
- 157-172
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- OpenAlex
- W3111509171
- Semantic Scholar
- ac0f894d379478905849bdc9574d08738caa6314
- Cited by
- 3,179
- References
- 76
- Citations by year
- 2026: 534 · 2025: 736 · 2024: 746 · 2023: 590 · 2022: 417 · 2021: 149 · 2020: 2 · 2012: 1
- FWCI
- 28.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical Research Council (MR/V007688/1)
- 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, microglial activation, amyloid-beta, tau pathology, amyloid hypothesis, innate immunity, microglial phenotype, microglial priming, disease trajectories, therapeutic target
- MeSH terms
- Neuroinflammatory Diseases, Alzheimer Disease, Brain, Humans, Macrophage Activation, Microglia, Neurodegenerative Diseases
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