Proteomics Analysis Identifying New Markers Related to Alzheimer’s Disease Pathology In Vivo

Abstract

AbstractBackgroundTo better understand the pathophysiological processes in Alzheimer’s disease (AD), we need to broaden our knowledge on molecular pathways and discover molecular markers that co‐occur with, precipitate and follow the accumulation beta‐amyloid (Aβ) and tau pathology. Using high‐throughput proteomics, we investigated how a wide array of proteins relate to AD pathology in a large cohort spanning the AD continuum.MethodWe included 949 BioFINDER‐2 participants with cerebrospinal fluid (CSF) measurements of 2943 proteins (Olink Explore 3072 assay), and CSF and/or PET measurements of Aβ and tau. We compared CSF proteins between groups based on their Aβ (A) and tau (T) status, defined respectively from CSF Aβ42/40 ratio and tau‐PET RO948 in the temporal meta‐ROI (i.e. A‐T‐ vs. A+T‐ and A+T‐ vs. A+T+). We also compared A+T+ vs. non‐AD neurodegenerative diseases. Then, among the significant proteins identified across all three comparisons, we evaluated their associations with Aβ‐ (flutemetamol) and tau‐PET, both cross‐sectionally and longitudinally (based on rate of change). These latter analyses were restricted to cognitively unimpaired and patients with MCI, who all had Aβ‐ and tau‐PET available (n = 548).ResultAcross all AT comparisons, 85 proteins were significantly different between groups (pFDR<0.05; Fig.1). More advanced pathology was associated with higher protein levels, except ApoE levels that were decreased. The A+T‐ vs. A+T+ comparison revealed most protein differences (n = 74; Fig.1B), compared to A‐T‐ vs. A+T‐ or A+T+ vs. non‐AD neurodegenerative diseases. In cross‐sectional analyses, 32/85 proteins (38%) were significantly associated with Aβ‐ and tau‐PET load, with the strongest ones being microtubule‐associated protein tau (MAPT), neurogranin (NRGN), ITGAM, ITGB2 and SMOC1. When putting both pathologies in the same model, all proteins remained associated with Aβ only, except for ENO2 and GPI, which remained associated with tau only (Table 1). In longitudinal analyses, 19 proteins were associated with greater tau‐PET rate of change (the top five being MAPT, NRGN, ITGB2, FABP3 and CHIT1), whereas only SMOC1 and ITGAM were associated with greater Aβ‐PET rate of change (Table 1).ConclusionThrough comprehensive proteomics analysis, we identified novel proteins associated with AD pathology, many of which are involved innate immunity, intracellular transport and extracellular matrix binding.