Deep proteome analysis of plasma reveals novel biomarkers of mild cognitive impairment and Alzheimer's disease: A longitudinal study

Abstract

Ageing is the primary risk factor for AD; however, there is a poor understanding of the biological mechanisms by which the ageing process contributes to the development of AD in some individuals, while others progress to advanced age with relatively little AD neuropathology. To halt the progression of AD, the preclinical stage of neurodegeneration (before the onset of clinical symptoms) is anticipated to be the more effective time point for applying potentially disease-modifying interventions in AD. The main objective of this study was to understand the age and disease related proteomic changes are detectable in plasma, based on retrospective analysis of longitudinal data and cross-sectional analyses of clinically diagnosed cases. We conducted an in-depth plasma proteomics analysis using intensive depletion of high-abundant plasma proteins using the Agilent multiple affinity removal liquid chromatography (LC) column-Human 14 (Hu14) followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE) technique. In this study, we have begun to address the following questions; (1) differences in plasma proteomic profiles between normal ageing, vs ageing with progress to cognitive decline (MCI) or disease (dementia, probable AD), (2) cross-sectional analysis of baseline data, when all subjects are clinically identified as cognitively normal, provides insight into the preclinical changes which precede subsequent progression to AD and potentially provide early biomarkers, and (3) comparison of plasma at the point of progression to clinically diagnosed onset of cognitive decline or AD, can provide potential plasma biomarkers to facilitate clinical diagnosis. Furthermore, our findings also identified some proteins previously discovered in AD CSF and brain proteomics signatures that could provide clinically meaningful information. We identified differentially expressed proteins which were associated with several biological and molecular processes that may serve as therapeutic targets and fluid biomarkers for the disease.