Integrating TSPO PET imaging and transcriptomics to unveil the role of neuroinflammation and amyloid-β deposition in Alzheimer's disease

Purpose Despite the revealed role of immunological dysfunctions in the development and progression of Alzheimer's disease (AD) through animal and postmortem investigations, direct evidence regarding the impact of genetic factors on microglia response and amyloid-beta (A beta) deposition in AD individuals is lacking. This study aims to elucidate this mechanism by integrating transcriptomics and TSPO, A beta PET imaging in clinical AD cohort.Methods We analyzed 85 patients with PET/MR imaging for microglial activation (TSPO, [18F]DPA-714) and A beta ([18F]AV-45) within the prospective Alzheimer's Disease Immunization and Microbiota Initiative Study Cohort (ADIMIC). Immune-related differentially expressed genes (IREDGs), identified based on AlzData, were screened and verified using blood samples from ADIMIC. Correlation and mediation analyses were applied to investigate the relationships between immune-related genes expression, TSPO and A beta PET imaging.Results TSPO uptake increased significantly both in aMCI (P < 0.05) and AD participants (P < 0.01) and showed a positive correlation with A beta deposition (r = 0.42, P < 0.001). Decreased expression of TGFBR3, FABP3, CXCR4 and CD200 was observed in AD group. CD200 expression was significantly negatively associated with TSPO PET uptake (r =-0.33, P = 0.013). Mediation analysis indicated that CD200 acted as a significant mediator between TSPO uptake and A beta deposition (total effect B = 1.92, P = 0.004) and MMSE score (total effect B =-54.01, P = 0.003).Conclusion By integrating transcriptomics and TSPO PET imaging in the same clinical AD cohort, this study revealed CD200 played an important role in regulating neuroinflammation, A beta deposition and cognitive dysfunction.