Proteome-based plasma biomarkers for Alzheimer's disease

Abstract

Alzheimer's disease is a common and devastating disease for which there is no readily available biomarker to aid diagnosis or to monitor disease progression. Biomarkers have been sought in CSF but no previous study has used two-dimensional gel electrophoresis coupled with mass spectrometry to seek biomarkers in peripheral tissue. We performed a case-control study of plasma using this proteomics approach to identify proteins that differ in the disease state relative to aged controls. For discovery-phase proteomics analysis, 50 people with Alzheimer's dementia were recruited through secondary services and 50 normal elderly controls through primary care. For validation purposes a total of 511 subjects with Alzheimer's disease and other neurodegenerative diseases and normal elderly controls were examined. Image analysis of the protein distribution of the gels alone identifies disease cases with 56% sensitivity and 80% specificity. Mass spectrometric analysis of the changes observed in two-dimensional electrophoresis identified a number of proteins previously implicated in the disease pathology, including complement factor H (CFH) precursor and alpha-2-macroglobulin (alpha-2M). Using semi-quantitative immunoblotting, the elevation of CFH and alpha-2M was shown to be specific for Alzheimer's disease and to correlate with disease severity although alternative assays would be necessary to improve sensitivity and specificity. These findings suggest that blood may be a rich source for biomarkers of Alzheimer's disease and that CFH, together with other proteins such as alpha-2M may be a specific markers of this illness.

Longitudinal Protein Changes in Blood Plasma Associated with the Rate of Cognitive Decline in Alzheimer’s Disease

“…SAP has been previously reported as a diagnostic AD candidate biomarker in the literature [4] albeit it with conflicting direction of association [3,10,30,31]. Although we found changes in SAP to be associated with rate of decline we did not observe significant changes of SAP when comparing diagnostic groups against controls.…”

“…We found a suggestive association between Albumin and the conversion from MCI to AD Albumin (p-value=0.010). Albumin has been previously associated with AD [3,9,32,39]. In a recent review, we found that Albumin was associated with an AD-related phenotype in four independent research cohorts [4].…”

“…Informed consent was obtained for all subjects according to the Declaration of Helsinki (1991), and protocols and procedures were approved by the relevant local ethical committees at each site. All subjects were assessed with a standardised assessment protocol including informant interview for diagnosis, cognitive assessment such as the Mini Mental State Examination (MMSE) together with standardised assessment of function, behaviour and dementia severity as previously reported [3,9,10].…”

“…Of particular note is the growing body of work around changes in plasma proteins in relation to AD and/or MCI-related protein biomarkers using Mass Spectrometry and antibody capture technologies [2][3][4][5][6][7][8][9][10].…”

Protein Bioinformatics Databases and Resources

“…Since proteins occupy a middle ground molecularly between gene and transcript and many higher levels of molecular and cellular structure and organization, and most physiological and pathological processes are manifested at the protein level, biological and biomedical scientists are increasingly interested in applying high-throughput proteomics techniques to achieve a better understanding of basic molecular biology and disease processes [4,5].…”