부산대학교 도서관

To date, the development of disease-modifying therapies for Alzheimer's disease (AD) has largely focused on the removal of amyloid beta A[beta] fragments from the CNS. Proteomic profiling of patient fluids may help identify novel therapeutic targets and biomarkers associated with AD pathology. Here, we applied the Olink[TM] ProSeek immunoassay to measure 270 CSF and plasma proteins across 415 A[beta]- negative cognitively normal individuals (A[beta]- CN), 142 A[beta]-positive CN (A[beta]+ CN), 50 A[beta]- mild cognitive impairment (MCI) patients, 75 A[beta]+ MCI patients, and 161 A[beta]+ AD patients from the Swedish BioFINDER study. A validation cohort included 59 A[beta]- CN, 23 A[beta]- + CN, 44 A[beta]- MCI and 53 A[beta]+ MCI. To compare protein concentrations in patients versus controls, we applied multiple linear regressions adjusting for age, gender, medications, smoking and mean subject-level protein concentration, and corrected findings for false discovery rate (FDR, q < 0.05). We identified, and replicated, altered levels of ten CSF proteins in A[beta]+ individuals, including CHIT1, SMOC2, MMP-10, LDLR, CD200, EIF4EBP1, ALCAM, RGMB, tPA and STAMBP (- 0.14 < d < 1.16; q < 0.05). We also identified and replicated alterations of six plasma proteins in A[beta]+ individuals OSM, MMP-9, HAGH, CD200, AXIN1, and uPA (- 0.77 < d < 1.28; q < 0.05). Multiple analytes associated with cognitive performance and cortical thickness (q < 0.05). Plasma biomarkers could distinguish AD dementia (AUC = 0.94, 95% CI = 0.87-0.98) and prodromal AD (AUC = 0.78, 95% CI = 0.68-0.87) from CN. These findings reemphasize the contributions of immune markers, phospholipids, angiogenic proteins and other biomarkers downstream of, and potentially orthogonal to, A[beta]- and tau in AD, and identify candidate biomarkers for earlier detection of neurodegeneration. Keywords: Alzheimer's disease, Mild cognitive impairment, Biomarker, Proteomics, Inflammation, Apoptosis, Angiogenesis
Author(s): Christopher D. Whelan[sup.1], Niklas Mattsson[sup.2,3], Michael W. Nagle[sup.4], Swetha Vijayaraghavan[sup.5], Craig Hyde[sup.4], Shorena Janelidze[sup.2], Erik Stomrud[sup.2], Julie Lee[sup.4], Lori Fitz[sup.4], Tarek A. Samad[sup.6], Gayathri Ramaswamy[sup.1], Richard A. Margolin[sup.7], Anders [...]