Identification of Novel Fluid Biomarkers for Alzheimer's Disease

OF THE DISSERTATION Identification of Novel Fluid Biomarkers for Alzheimer’s Disease by Rebecca June Craig-Schapiro Doctor of Philosophy in Biology and Biomedical Sciences Neurosciences Program Washington University in St. Louis, 2012 Dr. David M. Holtzman, Chairperson Clinicopathological studies suggest that Alzheimer’s disease (AD) pathology begins to appear ~10-20 years before the resulting cognitive impairment draws medical attention. Biomarkers that can detect AD pathology in its early stages and predict dementia onset and progression would, therefore, be invaluable for patient care and efficient clinical trial design. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) using an unbiased proteomics approach (twodimensional difference gel electrophoresis with liquid chromatography tandem mass spectrometry). From this, we identified 47 proteins that differed in abundance between cognitively normal (Clinical Dementia Rating [CDR] 0) and mildly demented (CDR 1) subjects. To validate these findings, we measured a subset of the identified candidate biomarkers by enzyme linked immunosorbent assay (ELISA); promising candidates in this discovery cohort (N=47) were further evaluated by ELISA in a larger validation CSF cohort (N=292) that contained an additional very mildly demented (CDR 0.5) group. Levels of four novel biomarkers were significantly altered in AD, and Receiver-operating characteristic (ROC) analyses using a stepwise logistic regression model identified optimal panels containing these markers that distinguished CDR 0 from CDR>0 (tau, YKL-40, NCAM) and CDR 1 from CDR<1 (tau, chromogranin-A, carnosinase-I). Plasma