Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease
Abstract To date, the development of disease-modifying therapies for Alzheimer’s disease (AD) has largely focused on the removal of amyloid beta Aβ fragments from the CNS. Proteomic profiling of patient fluids may help identify novel therapeutic targets and biomarkers associated with AD pathology. H...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-11-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-019-0795-2 |
| _version_ | 1819008555585372160 |
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| author | Christopher D. Whelan Niklas Mattsson Michael W. Nagle Swetha Vijayaraghavan Craig Hyde Shorena Janelidze Erik Stomrud Julie Lee Lori Fitz Tarek A. Samad Gayathri Ramaswamy Richard A. Margolin Anders Malarstig Oskar Hansson |
| author_facet | Christopher D. Whelan Niklas Mattsson Michael W. Nagle Swetha Vijayaraghavan Craig Hyde Shorena Janelidze Erik Stomrud Julie Lee Lori Fitz Tarek A. Samad Gayathri Ramaswamy Richard A. Margolin Anders Malarstig Oskar Hansson |
| author_sort | Christopher D. Whelan |
| collection | DOAJ |
| description | Abstract To date, the development of disease-modifying therapies for Alzheimer’s disease (AD) has largely focused on the removal of amyloid beta Aβ 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™ ProSeek immunoassay to measure 270 CSF and plasma proteins across 415 Aβ- negative cognitively normal individuals (Aβ- CN), 142 Aβ-positive CN (Aβ+ CN), 50 Aβ- mild cognitive impairment (MCI) patients, 75 Aβ+ MCI patients, and 161 Aβ+ AD patients from the Swedish BioFINDER study. A validation cohort included 59 Aβ- CN, 23 Aβ- + CN, 44 Aβ- MCI and 53 Aβ+ 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 Aβ+ 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 Aβ+ 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, Aβ- and tau in AD, and identify candidate biomarkers for earlier detection of neurodegeneration. |
| first_indexed | 2024-12-21T00:42:20Z |
| format | Article |
| id | doaj.art-d2b5bbd9197e4ce8a2ccfd4b15b135e3 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-21T00:42:20Z |
| publishDate | 2019-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-d2b5bbd9197e4ce8a2ccfd4b15b135e32022-12-21T19:21:39ZengBMCActa Neuropathologica Communications2051-59602019-11-017111410.1186/s40478-019-0795-2Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s diseaseChristopher D. Whelan0Niklas Mattsson1Michael W. Nagle2Swetha Vijayaraghavan3Craig Hyde4Shorena Janelidze5Erik Stomrud6Julie Lee7Lori Fitz8Tarek A. Samad9Gayathri Ramaswamy10Richard A. Margolin11Anders Malarstig12Oskar Hansson13Research and Early Development (RED), Biogen Inc.Clinical Memory Research Unit, Department of Clinical Sciences, Lund UniversityPfizer Worldwide Research & DevelopmentDepartment of Medicine, Karolinska InstitutetPfizer Worldwide Research & DevelopmentClinical Memory Research Unit, Department of Clinical Sciences, Lund UniversityClinical Memory Research Unit, Department of Clinical Sciences, Lund UniversityPfizer Worldwide Research & DevelopmentPfizer Worldwide Research & DevelopmentRare and Neurologic Disease Research, Sanofi Research and DevelopmentResearch and Early Development (RED), Biogen Inc.CNS Research Solutions LLCPfizer Worldwide Research & DevelopmentClinical Memory Research Unit, Department of Clinical Sciences, Lund UniversityAbstract To date, the development of disease-modifying therapies for Alzheimer’s disease (AD) has largely focused on the removal of amyloid beta Aβ 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™ ProSeek immunoassay to measure 270 CSF and plasma proteins across 415 Aβ- negative cognitively normal individuals (Aβ- CN), 142 Aβ-positive CN (Aβ+ CN), 50 Aβ- mild cognitive impairment (MCI) patients, 75 Aβ+ MCI patients, and 161 Aβ+ AD patients from the Swedish BioFINDER study. A validation cohort included 59 Aβ- CN, 23 Aβ- + CN, 44 Aβ- MCI and 53 Aβ+ 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 Aβ+ 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 Aβ+ 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, Aβ- and tau in AD, and identify candidate biomarkers for earlier detection of neurodegeneration.http://link.springer.com/article/10.1186/s40478-019-0795-2Alzheimer’s diseaseMild cognitive impairmentBiomarkerProteomicsInflammationApoptosis |
| spellingShingle | Christopher D. Whelan Niklas Mattsson Michael W. Nagle Swetha Vijayaraghavan Craig Hyde Shorena Janelidze Erik Stomrud Julie Lee Lori Fitz Tarek A. Samad Gayathri Ramaswamy Richard A. Margolin Anders Malarstig Oskar Hansson Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease Acta Neuropathologica Communications Alzheimer’s disease Mild cognitive impairment Biomarker Proteomics Inflammation Apoptosis |
| title | Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease |
| title_full | Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease |
| title_fullStr | Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease |
| title_full_unstemmed | Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease |
| title_short | Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease |
| title_sort | multiplex proteomics identifies novel csf and plasma biomarkers of early alzheimer s disease |
| topic | Alzheimer’s disease Mild cognitive impairment Biomarker Proteomics Inflammation Apoptosis |
| url | http://link.springer.com/article/10.1186/s40478-019-0795-2 |
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