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

Accepted version
Peer-reviewed

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Type

Article

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Authors

Westwood, Sarah 
Leoni, Emanuela 
Hye, Abdul 
Lynham, Steven 
Khondoker, Mizanur R 

Abstract

Increasingly, clinical trials for Alzheimer's disease (AD) are being conducted earlier in the disease phase and with biomarker confirmation using in vivo amyloid PET imaging or CSF tau and Aβ measures to quantify pathology. However, making such a pre-clinical AD diagnosis is relatively costly and the screening failure rate is likely to be high. Having a blood-based marker that would reduce such costs and accelerate clinical trials through identifying potential participants with likely pre-clinical AD would be a substantial advance. In order to seek such a candidate biomarker, discovery phase proteomic analyses using 2DGE and gel-free LC-MS/MS for high and low molecular weight analytes were conducted on longitudinal plasma samples collected over a 12-year period from non-demented older individuals who exhibited a range of 11C-PiB PET measures of amyloid load. We then sought to extend our discovery findings by investigating whether our candidate biomarkers were also associated with brain amyloid burden in disease, in an independent cohort. Seven plasma proteins, including A2M, Apo-A1, and multiple complement proteins, were identified as pre-clinical biomarkers of amyloid burden and were consistent across three time points (p <  0.05). Five of these proteins also correlated with brain amyloid measures at different stages of the disease (q <  0.1). Here we show that it is possible to detect a plasma based biomarker signature indicative of AD pathology at a stage long before the onset of clinical disease manifestation. As in previous studies, acute phase reactants and inflammatory markers dominate this signature.

Description

Keywords

KeywordsAlzheimer’s disease, amyloid, biological markers, blood, plasma, preclinical, proteomics, Aged, Alzheimer Disease, Amyloidogenic Proteins, Aniline Compounds, Benzothiazoles, Biomarkers, Brain, Brain Chemistry, Female, Humans, Male, Positron-Emission Tomography, Tandem Mass Spectrometry, Thiazoles, alpha-Macroglobulins

Journal Title

J Alzheimers Dis

Conference Name

Journal ISSN

1387-2877
1875-8908

Volume Title

52

Publisher

IOS Press
Sponsorship
Medical Research Council (G0801464)