Inflammation‐related proteomic changes in response to amyloid and tau pathologies

Abstract Background Emerging evidence underscores the importance of neuroinflammation in the progression of Alzheimer's disease (AD) pathophysiology. Recent studies indicate the involvement of inflammatory mechanisms in amyloid‐β (Aβ) and tau deposition in the brain. 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 inflammatory changes in AD has been challenging. With this study, we sought to characterize immune‐related proteins in cerebrospinal fluid (CSF) and plasma, in relation to Aβ and tau PET. Methods Participants from the Translational Biomarker for Aging and Dementia Cohort (TRIAD) incorporating within the AD spectrum, and with available Aβ PET ([ 18 F]AZD4694) and tau PET ([ 18 F]MK6240), had plasma ( n = 376) and CSF ( n = 277) samples analyzed with the NULISA technology (Alamar Biosciences®). A total of 309 inflammation‐related proteins were selected and included in our analysis. Validation cohorts were used to generalize the results: ADNI had CSF samples ( n = 384) analyzed with the SomaScan technology (SomaLogic ® ); and BBDP had plasma samples ( n = 253) analyzed with NULISA technology (Alamar Biosciences ® ). Standardized (Std) β coefficients from linear models relating Aβ‐ and tau‐PET SUVR (both included as independent variables) to the CSF and plasma protein levels. Models included age and sex and as covariates. Results Several proteins exhibit distinct patterns in relation to Aβ and tau pathologies. Notably, specific proteins show strong positive associations with global Aβ‐PET levels, independent of tau‐PET levels, while others are positively associated with global tau‐PET levels, independent of Aβ‐PET levels (Figure 1). Validation in ADNI (plasma data) and BBDP cohort (CSF data) confirmed these findings. A Venn diagram illustrates unique and shared significant proteins across different groups and matrices (Figure 2a). Furthermore, LOESS curves revealed that specific proteins increase or decrease along the disease pseudo‐time, highlighting their potential roles in disease progression (Figure 2b, 2c). Conclusion Overall, using a multi‐omics approach, this preliminary analysis provided new insights on key proteins and molecular inflammatory pathways that co‐occur with, and follow the accumulation of, Aβ and tau load along the AD continuum. This analysis will be further expanded and detailed in more cohorts.