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

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.

Fluid‐based proteomics targeted on pathophysiological processes and pathologies in neurodegenerative diseases

“…; Westwood et al . ). However, these data have not been replicated or examined in relation to neurodegenerative dementias other than AD and should presently be interpreted with caution.…”

Blood‐based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic

“…Another COU with high potential to aid in clinical trials is the identification of blood-based biomarkers that can identify those individuals with high (or low) likelihood of being amyloid positive[40–42]. Westwood and colleagues[40] recently examined proteomic markers among longitudinal plasma samples collected over a 12-year period among non-demented individuals with [11C]PiB PET scans available.…”

“…Westwood and colleagues[40] recently examined proteomic markers among longitudinal plasma samples collected over a 12-year period among non-demented individuals with [11C]PiB PET scans available. In this study, seven plasma proteins (including A2M, Apo-A1, and multiple complement proteins) were significantly associated with amyloid burden.…”

A blood-based signature of cerebrospinal fluid Aβ1–42status

“…To bypass the invasiveness of CSF collection, there is a strong interest in finding blood-based markers that yield the same information about amyloid status as would be obtained from CSF. There have been a number of studies which have shown that a blood protein signature can be found that reflects AD brain pathology as measured by PET [15][16][17][18][19][20][21][22][23][24] . Of particular interest is the recent study by Nakamura et al (2018) 25 , whereby levels of Aβ 1−40 , Aβ 1−42 and APP 669−771 in plasma, measured using specialised immunoprecipitation (IP) coupled with Matrix Assisted Laser Desorption/Ionization (MALDI) time-of -flight (TOF) mass spectrometry (MS) (henceforth referred to as IP-MALDI-TOF-MS), were shown in combination to have strong performance (> 0.94 area under the receiver operating characteristic curve (AUC)) in predicting PET Aβ 1−42 status across two cohorts.…”