Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer's disease

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.