Biomarkers.

Background: Emerging evidence underscores the importance of neuroinflammation in the progression of Alzheimer's disease (AD) pathophysiology. Recent studies indicate the involvement of the inflammatory mechanisms both in amyloid- β (Aβ) and tau deposition in the brain. Nevertheless, due to the complexity of the immune responses and the intricate interplay between the peripheral and the central nervous systems, identifying biomarkers that reflect the brain´s inflammatory state in AD has been a challenge. For this reason, the characterization of immune-related proteins in cerebrospinal fluid (CSF) and plasma would contribute to the understanding of the role of neuroinflammation in the progression of AD.

Method: Participants from the Translational Biomarker for Aging and Dementia Cohort (TRIAD) incorporating within the AD spectrum, and with available amyloid Aβ ([F]AZD4694), tau ([F]MK6240) and TSPO ([C]PBR28) PET data (positivity = 2.5 SD > mean ROI-SUVR of young participants), had plasma (n= 151) samples analyzed with the NULISA technology (Alamar Biosciences). Inflammation-related proteins (n=72) were selected and included in our analysis, which differential expression was evaluated with linear models (LIMMA) contrasting TSPO groups. After FDR correction for multiple comparisons, the differentially expressed proteins were selected for further analysis, where protein levels were correlated with the PET uptake of 45 anatomical brain regions.

Result: The differential expression analysis unveiled 5 proteins that are in higher concentrations in the plasma of TSPO positive in comparison with TSPO negative participants (Figure 1): GFAP, CHI3L1, CST3, FABP3, and CHIT1. The correlation analysis between the plasmatic proteins and PET uptake showed significant overlapping correlations with TSPO, Aβ and tau PET in brain regions such as inferior frontal gyrus, inferior occipital gyrus and amygdala (Figure 2).

Conclusion: These preliminary findings underscore the relevance of GFAP, CHI3L1, CST3, FABP3, and CHIT1 at proxying immune-related processes in AD, by linking peripherally quantified proteins to brain pathology, as suggested by the colocalized correlations with amyloid, tau and TSPO PET uptake. Further replication of this analysis on the CSF proteomic data of these participants will support the potential significance of these proteins as valuable indicators of neuroinflammation in AD pathology.