Longitudinal blood based biomarkers of Alzheimer’s disease pathology in healthy elderly individuals

Student thesis: Doctoral ThesisDoctor of Philosophy


There is an urgent need for Alzheimer´s disease (AD) biomarkers that can detect the disease at the early pre-symptomatic stages. Case versus control study designs often ignore clinical heterogeneity in patients and neuropathology in controls resulting in markers with doubtful clinical utility. Using markers of in vivo β-amyloid deposition (e.g. 11C-PiB) combined with positron emission tomography (PET) or MRI to derive biologically relevant biomarkers associated with established endophenotypes of disease pathology is a better approach. Neuropathological hallmarks of AD (β-amyloid plaques and neurofibrillary tangles) are commonly reported in post-mortem brains of non-demented elderly individuals, suggesting these cases might represent preclinical AD and may be a good population in which to detect early AD biomarkers. Here we aimed to identify plasma biomarkers associated with AD endophenotypes of brain amyloid burden or brain atrophy in non-demented older individuals using two complimentary longitudinal discovery-phase proteomic analyses. Two-dimensional gel electrophoresis coupled with mass spectrometry was performed on longitudinal plasma samples from non-demented older individuals exhibiting a range of 11C-PiB PET measures of amyloid load. The relationship between protein levels and measures of brain atrophy, cognitive decline, and amyloid load were examined. A label-free LC-MS/MS approach targeted at low molecular weight proteins (<30kDa) was also performed on a subset of these subjects to enhance coverage of the plasma proteome. Validation of candidate biomarkers was performed in an independent cohort using quantitative immunoassays and aptamer-based arrays. We have identified 15 plasma proteins associated with brain amyloid load, brain atrophy and cognitive scores. Our longitudinal study design allowed us to explore dynamic changes in concentrations of plasma protein profiles in relation to rates of change in both measures of AD pathology and cognition. Validation experiments determined whether these candidate biomarkers of pathology performed in an AD cohort.
Date of Award2014
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorAngela Hodges (Supervisor) & Simon Lovestone (Supervisor)

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