Blood protein predictors of brain amyloid for enrichment in clinical trials?

Abstract

BackgroundMeasures of neocortical amyloid burden (NAB) identify individuals who are at substantially greater risk of developing Alzheimer's disease (AD). Blood-based biomarkers predicting NAB would have great utility for the enrichment of AD clinical trials, including large-scale prevention trials.MethodsNontargeted proteomic discovery was applied to 78 subjects from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing with a range of NAB values. Technical and independent replications were performed by immunoassay.ResultsSeventeen discovery candidates were selected for technical replication. α2-Macroglobulin, fibrinogen γ-chain (FGG), and complement factor H-related protein 1 were confirmed to be associated with NAB. In an independent cohort, FGG plasma levels combined with age predicted NAB had a sensitivity of 59% and specificity of 78%.ConclusionA single blood protein, FGG, combined with age, was shown to relate to NAB and therefore could have potential for enrichment of clinical trial populations.

Blood-Based Biomarker Candidates of Cerebral Amyloid Using PiB PET in Non-Demented Elderly

“…TMT combined with LC-MS/MS is an approach that allows the use of the same methodology to analyze proteins but now multiplexed with up to six samples including a reference sample simultaneously. This approach had previously been performed by Ashton et al [7] on 78 samples from the AIBL study; TMT LC-MS/MS had been performed on all samples and after a stringent data clean up procedure (detailed in Ashton et al [7]) 381 protein MW isoforms were confidently measured, representing 116 unique protein groups. Of our 7 candidate biomarkers from the discovery phase analyses all but one (Complement C4b) were detected in this dataset.…”

“…This study further examined pre-existing proteomic data from 78 subjects from the AIBL study, generated by Ashton et al [7], which included; 19 healthy controls, 31 subjective memory complaints (SMC), 22 mild cognitive impairment (MCI), and 6 AD patients, all of which had undergone 11 C-PiB PET scans. Detailed diagnostic criteria and further cohort information is available in Ellis et al [18].…”

“…TMT 6Plex (Thermo Scientific) combined with LC-MS-MS therefore allows the use of the same methodology as in gel-free LC-MS/MS discovery phase experiments but now multiplexed with up to six samples including a reference sample measured simultaneously. Ashton et al [7] had previously performed TMT 6Plex LC-MS/MS on 78 samples from the AIBL study, and therefore this pre-existing dataset was here further analyzed. Protein identifications observed in different gel fractions were considered as separate entities defined as protein MW isoforms.…”

“…Extension study data was obtained from a preexisting dataset generated by Ashton et al (2015) [7]. Briefly, protein MW isoforms had undergone the following statistical tests; Mann-Whitney U test and logistic regression (PiB+ and PiB− group comparison) and Spearman Rank Correlation (SRC) and linear regression (associations with PiB retention as a continuous measure).…”

“…Plasma proteins were assessed for their relationship to global brain amyloid load at three time points; 12 years before in vivo amyloid PET imaging, 6 years before amyloid PET imaging, and concurrently to amyloid PET imaging. Proteins that were consistently associated with amyloid PET at all three time points were investigated further as candidate biomarkers throughout the disease in an independent cohort, using pre-existing data generated by Ashton et al [7]. …”