Neuroinflammation is independently associated with brain network dysfunction in Alzheimer's disease
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Updated: Aug 18, 2025
Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Fangda Leng1,2, Rainer Hinz3, Steve Gentleman1
1Department of Brain Sciences, Imperial College London, London, UK.
Abstract:
Brain network dysfunction is increasingly recognised in Alzheimer's disease (AD). However, the causes of brain connectivity disruption are still poorly understood. Recently, neuroinflammation has been identified as an important factor in AD pathogenesis. Microglia participate in the construction and maintenance of healthy neuronal networks, but pro-inflammatory microglia can also damage these circuits. We hypothesised that microglial activation is independently associated with brain connectivity disruption in AD. We performed a cross-sectional multimodal imaging study and interrogated the relationship between imaging biomarkers of neuroinflammation, Aβ deposition, brain connectivity and cognition. 42 participants (12 Aβ-positive MCI, 14 Aβ-positive AD and 16 Aβ-negative healthy controls) were recruited. Participants had 11C-PBR28 and 18F-flutemetamol PET to quantify Aβ deposition and microglial activation, T1-weighted, diffusion tensor and resting-state functional MRI to assess structural network and functional network. 11C-PBR28 uptake, structural network integrity and functional network orgnisation were compared across diagnostic groups and the relationship between neuroinflammation and brain network was tested in 26 Aβ-positive patients. Increased 11C-PBR28 uptake, decreased FA, network small-worldness and local efficiency were observed in AD patients. Cortical 11C-PBR28 uptake correlated negatively with structural integrity (standardised β = -0.375, p = 0.037) and network local efficiency (standardised β = -0.468, p < 0.001), independent of cortical thickness and Aβ deposition, while Aβ was not. Network structural integrity, small-worldness and local efficiency, and cortical thickness were positively associated with cognition. Our findings suggest cortical neuroinflammation coincide with structural and functional network disruption independent of Aβ and cortical atrophy. These findings link the brain connectivity change and pathological process in Alzheimer's disease, and suggest a pathway from neuroinflammation to systemic brain dysfunction.
Insights
Neuroinflammation, not amyloid plaques, is linked to brain network disruption in Alzheimer's disease (AD). This study shows that microglial activation correlates with impaired brain connectivity, suggesting a pathway from inflammation to AD dysfunction.
Area of Science:
- Neuroscience
- Neurology
- Medical Imaging
Background:
- Brain network dysfunction is a hallmark of Alzheimer's disease (AD), but its underlying causes remain unclear.
- Neuroinflammation, involving microglia, is increasingly recognized as a key factor in AD pathogenesis.
- Pro-inflammatory microglia can disrupt healthy neuronal circuits, contributing to disease progression.
Purpose of the Study:
- To investigate the independent association between microglial activation and brain connectivity disruption in Alzheimer's disease.
- To explore the relationship between neuroinflammation, amyloid-beta (Aβ) deposition, brain network integrity, and cognitive function.
- To differentiate the roles of neuroinflammation and Aβ in AD-related network changes.
Main Methods:
- A cross-sectional multimodal imaging study involving 42 participants (Aβ-positive MCI, Aβ-positive AD, and Aβ-negative controls).
- Utilized PET imaging (¹¹C-PBR28 for microglial activation, ¹⁸F-flutemetamol for Aβ deposition) and MRI (T1-weighted, diffusion tensor, resting-state functional MRI) to assess brain structure and function.
- Analyzed correlations between neuroinflammation markers, Aβ load, network properties (structural integrity, functional organization), and cognitive scores.
Main Results:
- Alzheimer's disease patients exhibited increased microglial activation (¹¹C-PBR28 uptake) and decreased network integrity (FA, small-worldness, local efficiency).
- Cortical microglial activation negatively correlated with structural integrity and local network efficiency, independent of cortical thickness and Aβ deposition.
- Aβ deposition did not show a similar independent association with network disruption.
Conclusions:
- Cortical neuroinflammation is associated with structural and functional brain network disruption in Alzheimer's disease, independent of Aβ pathology and atrophy.
- These findings highlight a potential pathway from neuroinflammation to widespread brain dysfunction in AD.
- Targeting neuroinflammation may offer a therapeutic strategy for mitigating network disruption and cognitive decline in Alzheimer's disease.
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