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Abstract
Purpose: With the move towards development of disease modifying treatments, there is a need for a more specific early diagnosis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Plasma biomarkers are likely to play an important role in this. This thesis comprises a series of studies to examine established and novel plasma biomarkers of cognitive disorders, in particular MCI and AD, and their progression.
Methods: A meta-analysis was undertaken to evaluate whether plasma amyloid beta (Aβ) levels are an appropriate biomarker in cross-sectional and longitudinal studies of AD. A proteomics approach was then used to screen for MCI and AD protein biomarkers in pooled plasma in a cohort of 280 MCI, 19 AD and 411 cognitively normal subjects. Based on the proteomics data, multiplex bead immunoassay techniques were used to validate targeted protein biomarkers in individual samples.
Results: Meta-analysis results showed that in longitudinal studies cognitively normal individuals who converted to AD had higher baseline Aβ1-40 and Aβ1-42 levels, and a non-significantly increased Aβ1-42/ Aβ1-40 ratio. Systematic review suggests a model of differential longitudinal changes in plasma Aβ levels in cognitively stable individuals versus those who go on to develop AD dementia. A proteomics study using isobaric tags for relative and absolute quantitation (iTRAQ) showed 30 proteins significantly dysregulated in MCI and AD, including ApoA1, ApoA2, ApoB100, ApoH, ApoJ (clusterin), vitamin D binding protein (VDBP), Ig mu chain C region (IGHM) and afamin. Western blot results confirmed iTRAQ results: IGHM was increased and afamin was decreased in the MCI and AD groups. A group of seven apolipoproteins, β2 microglobulin, haptoglobin, C-reactive protein and VDBP were assayed by multiplex assays. Lower ApoA1, ApoA2 and ApoH levels, and a higher ApoB/ApoA1 ratio, increased the risk of cognitive decline over two years in cognitively normal individuals. ApoA1 was the most significant predictor of decline. These associations remained after statistically controlling for the lipid profile. Higher ApoJ levels predicted white matter atrophy over two years. VDBP was associated with cognitive decline in female patients.
Conclusion: Plasma Aβ1-40 and Aβ1-42 levels should be further explored as potential biomarkers. Proteomic approaches are promising techniques for screening for biomarkers. Although these findings need to be validated in different populations, they suggest that ApoA1, ApoH, ApoJ and VDBP can be considered as clinical biomarkers for cognitive impairment. Dysregulation of these proteins provides new clues to the possible pathogenesis of AD.