AUTHOR=Westwood Sarah , Baird Alison L. , Hye Abdul , Ashton Nicholas J. , Nevado-Holgado Alejo J. , Anand Sneha N. , Liu Benjamine , Newby Danielle , Bazenet Chantal , Kiddle Steven J. , Ward Malcolm , Newton Ben , Desai Keyur , Tan Hehir Cristina , Zanette Michelle , Galimberti Daniela , Parnetti Lucilla , Lleó Alberto , Baker Susan , Narayan Vaibhav A. , van der Flier Wiesje M. , Scheltens Philip , Teunissen Charlotte E. , Visser Pieter Jelle , Lovestone Simon 

TITLE=Plasma Protein Biomarkers for the Prediction of CSF Amyloid and Tau and [18F]-Flutemetamol PET Scan Result

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=10

YEAR=2018

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2018.00409

DOI=10.3389/fnagi.2018.00409

ISSN=1663-4365

ABSTRACT=<p><bold>Background:</bold> Blood biomarkers may aid in recruitment to clinical trials of Alzheimer’s disease (AD) modifying therapeutics by triaging potential trials participants for amyloid positron emission tomography (PET) or cerebrospinal fluid (CSF) Aβ and tau tests.</p><p><bold>Objective:</bold> To discover a plasma proteomic signature associated with CSF and PET measures of AD pathology.</p><p><bold>Methods:</bold> Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based proteomics were performed in plasma from participants with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD, recruited to the Amsterdam Dementia Cohort, stratified by CSF Tau/Aβ<sub>42</sub> (<italic>n</italic> = 50). Technical replication and independent validation were performed by immunoassay in plasma from SCD, MCI, and AD participants recruited to the Amsterdam Dementia Cohort with CSF measures (<italic>n</italic> = 100), MCI participants enrolled in the GE067-005 study with [<sup>18</sup>F]-Flutemetamol PET amyloid measures (<italic>n</italic> = 173), and AD, MCI and cognitively healthy participants from the EMIF 500 study with CSF Aβ<sub>42</sub> measurements (<italic>n</italic> = 494).</p><p><bold>Results:</bold> 25 discovery proteins were nominally associated with CSF Tau/Aβ<sub>42</sub> (<italic>P</italic> &lt; 0.05) with associations of ficolin-2 (FCN2), apolipoprotein C-IV and fibrinogen β chain confirmed by immunoassay (<italic>P</italic> &lt; 0.05). In the GE067-005 cohort, FCN2 was nominally associated with PET amyloid (<italic>P</italic> &lt; 0.05) replicating the association with CSF Tau/Aβ<sub>42</sub>. There were nominally significant associations of complement component 3 with PET amyloid, and apolipoprotein(a), apolipoprotein A-I, ceruloplasmin, and PPY with MCI conversion to AD (all <italic>P</italic> &lt; 0.05). In the EMIF 500 cohort FCN2 was trending toward a significant relationship with CSF Aβ<sub>42</sub> (<italic>P</italic> ≈ 0.05), while both A1AT and clusterin were nominally significantly associated with CSF Aβ<sub>42</sub> (both <italic>P</italic> &lt; 0.05).</p><p><bold>Conclusion:</bold> Associations of plasma proteins with multiple measures of AD pathology and progression are demonstrated. To our knowledge this is the first study to report an association of FCN2 with AD pathology. Further testing of the proteins in larger independent cohorts will be important.</p>