Utilizing Plasma Proteomics to Identify Novel Biomarkers of Cognitive Aging

Abstract

Alzheimer’s disease causes significant cognitive impairment, but current therapeutic approaches targeting core Alzheimer’s disease pathology have not provided clinically meaningful improvements in cognition. There is strong evidence suggesting parallel or ‘concomitant’ pathologies, such as vascular dysfunction, contribute to cognitive decline. To achieve clinically meaningful improvement in cognition, there is a dire need to develop multi-faceted approaches to prevention and treatment of cognitive decline to target concomitant risk pathways alongside efforts targeting core AD pathology. Identifying novel plasma biomarkers predictive of adverse cognitive aging would greatly aid in these efforts by identifying novel therapeutic targets. This dissertation project was designed to contribute to biomarker discovery efforts with a two-pronged approach to (1) perform hypothesis-driven candidate protein analyses, based on prior literature, to characterize associations the VWF-ADAMTS13 axis and cognition, and (2) perform hypothesis-generating discovery analyses to identify novel biomarkers for adverse cognitive aging. Lower baseline levels of ADAMTS13 were found to relate to faster rates of cognitive decline globally over longitudinal follow-up, and several promising plasma proteins and biological networks were identified through discovery analyses as relating to longitudinal cognitive trajectory.