PROJECT SUMMARY Alzheimer’s disease (AD), a leading cause of morbidity and mortality in older adults, causes significant cognitive impairment, but current therapeutic approaches targeting core AD 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. Approximately 80% of AD patients at autopsy have evidence of co-occurring vascular pathology, and detectable vascular dysfunction predates detectable changes in traditional AD biomarkers. Associations between vascular risk and cognitive decline appear most pronounced in individuals with early or mid-life exposure to vascular risk factors prior to onset of overt cognitive impairment, suggesting that vascular risk may drive early cognitive decline and contribute to or exacerbate the effects of core AD pathology. 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, such as vascular risk, 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, but few plasma proteomic studies of AD to date have focused on early clinical changes, examined disease progression, or replicated results. This F30 proposal aims to fill those gaps by (a) focusing on participants with normal cognition and mild cognitive impairment, a prodromal form of AD, (b) examining longitudinal cognitive outcomes, and (c) replicating all results in a separate cohort. Leveraging these novel strengths, the applicant will take a two-pronged approach to (1) perform hypothesis-driven candidate protein analyses, based on prior literature and preliminary data, to characterize associations between ADAMTS13 and cognition, and (2) perform hypothesis-generating discovery analyses to identify novel biomarkers for adverse cognitive aging. Pursuing two distinct but complementary approaches offers a unique training opportunity to develop skills and methodologic approaches for working with ‘omics data and will directly contribute to efforts to identify novel biomarkers and therapeutic targets for adverse cognitive aging. The proposed research will leverage the rich resources of the Vanderbilt Memory & Alzheimer’s Center. The research will be guided by an interdisciplinary mentorship team, including experts in neuropsychology, neuroscience, plasma proteomics, cardiovascular medicine, and AD. The parallel training plan will facilitate the candidate’s acquisition of the necessary knowledge and skills to propel her into a successful career as an independent physician-scientist bridging clinical cardiovascular medicine and cognitive aging research. Findings from this F30 proposal will provide valuable insight into the role of ADAMTS13 in cognitive decline and aid in the identification of novel plasma biomarkers predictive of early cognitive decline.

PROJECT NARRATIVE Alzheimer’s disease (AD), a leading cause of morbidity and mortality in older adults, causes significant cognitive impairment, but current therapeutic efforts have not provided clinically meaningful improvements in cognition. The proposed research will use plasma proteomic methodologies to identify novel plasma biomarkers predictive of early cognitive decline in older adults without clinical dementia or stroke. Findings from this proposal will aid in identification of novel therapeutic targets for prevention and treatment of cognitive decline and AD.