Neuroinflammation is independently associated with brain network dysfunction in Alzheimer's disease

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, A beta deposition, brain connectivity and cognition. 42 participants (12 A beta-positive MCI, 14 A beta-positive AD and 16 A beta-negative healthy controls) were recruited. Participants had C-11-PBR28 and F-18-flutemetamol PET to quantify A beta deposition and microglial activation, T1-weighted, diffusion tensor and resting-state functional MRI to assess structural network and functional network. C-11-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 A beta-positive patients. Increased C-11-PBR28 uptake, decreased FA, network small-worldness and local efficiency were observed in AD patients. Cortical C-11-PBR28 uptake correlated negatively with structural integrity (standardised beta = -0.375, p = 0.037) and network local efficiency (standardised beta = -0.468, p < 0.001), independent of cortical thickness and A beta deposition, while A beta 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 A beta 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.