Proteome-Based Plasma Markers of Brain Amyloid-β Deposition in Non-Demented Older Individuals

Abstract

Blood-based markers reflecting core pathological features of Alzheimer’s disease (AD) in pre-symptomatic individuals are likely to accelerate the development of disease-modifying treatments. Our aim was to discover plasma proteins associated with brain amyloid-beta (Aβ) burden in non-demented older individuals. We performed discovery-phase experiments using two dimensional gel electrophoresis (2DGE) and mass spectrometry-based proteomic analysis of plasma in combination with 11C-PiB PET imaging of the brain in samples collected 10 years prior to the PET scans. Confirmatory studies used ELISA assays in a separate set of blood samples obtained within a year of the PET scans. We observed that a panel of 18 2DGE plasma protein spots effectively discriminated between individuals with high and low brain Aβ. Mass spectrometry identified these proteins, many of which have established roles in Aβ clearance, including a strong signal from apolipoprotein-E (apoE). In validation-phase studies, we observed a strong association between plasma apoE concentration and Aβ burden in the medial temporal lobe. Targeted voxel-based analysis localized this association to the hippocampus and entorhinal cortex. APOE ε4 carriers also showed greater Aβ levels in several brain regions relative to ε4 non-carriers. These results suggest that both peripheral concentration of apoE protein and APOE genotype are related to early neuropathological changes in brain regions vulnerable to AD pathology even in the non-demented elderly. Our strategy combining proteomics with in vivo brain amyloid imaging holds promise for the discovery of biologically relevant peripheral markers in those at risk for AD.

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

“…All five of these proteins have been previously identified in plasma as candidate biomarkers associated with AD disease status and/or pathology [4, 9, 22–27]. In fact α2M and C3 are two of the most reproducible plasma protein markers of AD, associating with AD-related phenotypes in five independent cohorts [5].…”

“…Therefore a peripheral measure may also be a valuable biomarker in the preclinical stages. In 2013, for example, we reported a protein signature in nondemented elderly people from the Baltimore Longitudinal Study of Ageing (BLSA) that could differentiate between individuals who would go on to show amyloid pathology using PET imaging ten years later [9]. In the present study, we aimed to expand upon this work by increasing the coverage of the proteome investigated and by identifying proteins that are stable in their ability across time to reflect amyloid as a continuous measure in cognitively healthy individuals.…”

Evaluation of Plasma Proteomic Data for Alzheimer Disease State Classification and for the Prediction of Progression From Mild Cognitive Impairment to Alzheimer Disease

“…There have been previous attempts to use arrays of peripheral biomarkers, with mixed results. [28][29][30][31][32] For example, the initial promising results of an 18-analyte signature developed on 83 patients 33 did not show good diagnostic accuracy on a subsequent separate set of subjects. 30 Most of the previous studies of arrays of plasma markers were either too small to detect differences or did not use powerful enough computational approaches to detect differences in the populations of proteins.…”

Low Plasma ApoE Levels Are Associated with Smaller Hippocampal Size in the Alzheimer's Disease Neuroimaging Initiative Cohort

“…Three studies have examined the relationship of plasma ApoE levels and positron emission tomography (PET) imaging of Aβ deposits using Pittsburgh Compound B (PiB) [7,16,17]. Analyses of data collected in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Australian Imaging, Biomarkers, and Lifestyle (AIBL) studies found that lower plasma ApoE levels correlated with increased global cortical PiB retention on PET imaging [7,16].…”

“…Analyses of data collected in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Australian Imaging, Biomarkers, and Lifestyle (AIBL) studies found that lower plasma ApoE levels correlated with increased global cortical PiB retention on PET imaging [7,16]. However, in a smaller cohort of non-demented individuals enrolled in the Baltimore Longitudinal Study of Aging (BLSA), higher plasma ApoE levels correlated with increased PiB retention in medial temporal lobe regions [17]. …”