Abstract
Background: 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.Objective: To discover a plasma proteomic signature associated with CSF and PET measures of AD pathology.Methods: 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/Aβ42 (n = 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 (n = 100), MCI participants enrolled in the GE067-005 study with [18F]-Flutemetamol PET amyloid measures (n = 173), and AD, MCI and cognitively healthy participants from the EMIF 500 study with CSF Aβ42 measurements (n = 494).Results: 25 discovery proteins were nominally associated with CSF Tau/Aβ42 (P < 0.05) with associations of ficolin-2 (FCN2), apolipoprotein C-IV and fibrinogen β chain confirmed by immunoassay (P < 0.05). In the GE067-005 cohort, FCN2 was nominally associated with PET amyloid (P < 0.05) replicating the association with CSF Tau/Aβ42. 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 P < 0.05). In the EMIF 500 cohort FCN2 was trending toward a significant relationship with CSF Aβ42 (P ≈ 0.05), while both A1AT and clusterin were nominally significantly associated with CSF Aβ42 (both P < 0.05).Conclusion: 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.
Highlights
The accumulation of amyloid-beta (Aβ) plaques followed by the deposition of hyper-phosphorylated tau protein in neurofibrillary tangles, central to Alzheimer’s disease (AD) neuropathology, is thought to develop around 20 to 30 years in advance of clinical symptom onset (Jansen et al, 2015)
We utilized plasma from AD, mild cognitive impairment (MCI) and cognitively healthy control individuals sourced through the European Medical Information Framework (EMIF) platform1 who had a cerebrospinal fluid (CSF) Aβ42 measure, here we focused on measuring protein markers of AD pathology identified in the discovery and replication phase and from our previous studies
We used immunocapture to replicate these and previous findings in a cohort derived from a clinical trial of a radiotracer for detection of brain amyloid (GE067-005 study) and an independent validation phase study, again using immunocapture methods in an independent set of samples collated from three separate cohorts sourced using the EMIF
Summary
The accumulation of amyloid-beta (Aβ) plaques followed by the deposition of hyper-phosphorylated tau protein in neurofibrillary tangles, central to Alzheimer’s disease (AD) neuropathology, is thought to develop around 20 to 30 years in advance of clinical symptom onset (Jansen et al, 2015). To date there has been a relatively low rate of replication of these biomarkers across the field This may be in part due to issues surrounding a study design that compares AD to cognitively healthy elderly control subjects. Given that AD neuropathology precedes clinical presentation of the disease by a number of years, some cognitively healthy elderly subjects may be harboring silent AD neuropathology This reduces the ability to find biomarkers relating to AD using this design, as some control subjects will instead be preclinical cases. 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
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