Jaeger PA, Lucin KM, Britschgi M, Vardarajan B, Huang RP, Kirby ED, Abbey R, Boeve BF, Boxer AL, Farrer LA, Finch N, Graff-Radford NR, Head E, Hoffree M, Huang R, Johns H, Karydas A, Knopman DS, Loboda A, Masliah E, Narasimhan R, Petersen RC, Podtelezhnikov A, Pradhan S, Rademakers R, Sun CH, Younkin SG, Miller BL, Ideker T, Wyss-Coray T. Network-driven plasma proteomics expose molecular changes in the Alzheimer's brain. Mol Neurodegener. 2016 Apr 26;11:31. PubMed.

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  1. Traditional biomarker discovery studies in AD have relied upon a case–versus-control design wherein the binary discrimination of presence/absence of disease based on single analytes is the primary outcome. There are several limitations to this approach, including ignoring the significant levels of AD pathology in non-demented controls and a long preclinical prodrome of AD where pathology is accumulating in the brain prior to symptom onset. These studies also ignore the considerable heterogeneity in disease progression and symptoms in AD patients. For these reasons, single analyte markers arising from these case versus control studies have been notoriously difficult to replicate.

    The novel aspect of the present study is the use of a network approach, wherein both differential expression of individual proteins as well as the co-expression of multiple proteins within networks representing biological pathways relevant to AD pathogenesis are considered important. Secondly, the authors have used a systems-level approach, integrating data from multiple publicly available genome-wide association studies as well as gene expression datasets from brain to demonstrate a biological validation of their biomarker signals. Thirdly, rather than relying entirely on the binary discrimination between cases and controls, the authors used an endophenotype, i.e., a measure of global cognition represented by the MMSE score as an outcome variable to test associations with their biomarkers of interest.

    The study design is novel and cleverly leverages large datasets in the public domain to establish biologically plausible protein markers of AD arising from their index antibody array experiments. These pathways contain several of the “usual suspects” reported previously in other AD biomarker studies such as Complement C3, Haptoglobin, and Complement Factor H—a fact that provides a measure of confidence in the robustness of the results. A novel protein marker, GDF, also emerges from these analyses and merits independent validation in larger samples from different cohorts. 

    In order to reach clinical utility, such biomarkers require extensive independent validation. The immediate implications of studies such as this are the expansion of our knowledge of novel disease mechanisms that may potentially be targets for disease modification in AD.

    View all comments by Madhav Thambisetty

  2. The recent report by Jaeger and colleagues represents an exciting addition to current knowledge on plasma markers for AD. They present a comprehensive multi-level analysis pipeline to identify three biological pathways likely associated with AD: TGFβ/GDF/BMP signaling, apoptosis, and the complement system. By comparing and contrasting their results to those discovered in an alternative neurodegenerative disease (semantic-variant primary progressive aphasia, a sub-type of frontotemporal lobe dementia) they provide an essential validation of the findings; however, extension of this to other neurodegenerative diseases would be of equal importance in assessing validity. With early, prognostic identification of AD sufferers representing the “Holy Grail” for plasma biomarkers, further longitudinal evaluation will be required to gain a true indication of the potential clinical efficacy represented by these findings.

    View all comments by Samantha Burnham

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