Systematic Characterization of Heterogeneity caused by Neuroinflammation in Alzheimer’s Disease based on Integrative Network Analysis

Background: Alzheimer's disease (AD) is the most common cause of dementia. As a heterogenous disease, there are several clinically and pathobiological defined subtypes with different molecular signatures. Neuroinflammation contributed to AD pathogenesis, however, the roles it played in the heterogeneity of AD was unclear. Objective: We aimed to illustrate the roles neuroinflammation played in the heterogeneity of AD. Method: An integrative network analysis based on transcriptomics, miRNOmics, and proteomics was performed to illustrate the heterogeneous characters of AD. Combined-functional-networks and hypothesis-network were constructed and analyzed to explore the roles neuroinflammation played in AD heterogeneity. Results: Astrocytes, microglia, ‘M2 macrophage-Neuron’, and ‘Microglia- Neuron’ were shown to be enriched in neuroinflammation related functional terms in a cell- and spatial-specific way. The microglia and neurons could interact with each other in three different ways including indirect interactions via intermediate cells, indirect interactions via soluble factors, and direct interactions established localized and functionally distinct signaling, all of which were used to control different biological processes. The combined network analyses exhibited the key roles neuroinflammation plays in the 'AD hypothesis network’. Conclusion : The AD heterogeneity may be caused by the heterogeneous cells involved in neuroinflammation and the crosstalks between spatial-specific molecular signatures.