The Proteomic Signature of Dual Decline in Gait and Cognition
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Project Summary. It is well-accepted that altered gait can precede the clinical diagnosis of cognitive impairment and is a significant risk factor for cognitive decline. Older adults with combined altered gait and cognitive changes (dual-decline) are at greater risk of developing dementia than older adults with changes in only gait or cognition and stable function. Dual-decline incidence is high, estimated to have a pooled prevalence of 10.2% of older adults, and is additionally impactful because altered gait in those with Alzheimer’s disease (AD) and related dementias (ADRD), and leads to more frequent and injurious falls and greater healthcare costs. Unfortunately, an important knowledge gap persists regarding the pathophysiological changes that link declines in gait with dementia. There is a critical need to identify underlying pathophysiological changes to improve early detection and inform interventions for the dual-decline population. The overall objective of this application is to use a systems biology approach of proteomics to understand the pathophysiological changes associated with dual decline. Recent advances in proteomics technology have contributed to many breakthroughs in disease-related biomarker discovery and in understanding the pathways contributing to increased disease risk. Plasma proteomics has identified both AD-related proteins and altered gait-related proteins in cognitively unimpaired cohorts with potentially overlapping pathways. The proteome of dual decline, however, has not yet been determined. We will leverage a deeply phenotyped cohort, the Vanderbilt Memory and Aging Project (VMAP), with plasma proteomics (Olink Explorer 3072) at study entry and repeat measures of clinical gait speed, actigraphy, and neuropsychological assessments. This study proposes both cross-sectional (Aim 1) and longitudinal methods (Aim 2) to examine the unique proteome of dual decline. In each aim, we will also investigate gait changes derived from clinically measured gait speed (clinical gait) and gait characteristics extracted from actigraphy during everyday living (free-living gait). Free- living gait differs from clinically measured gait and may provide additional novel insights into the etiology of dual decline. Analyses will then be replicated in the Baltimore Longitudinal Study on Aging and compared with dual decline proteins and pathways identified in the VMAP cohort. Discovery of a unique proteome may identify predictors and treatment targets, potentially transforming early detection and intervention strategies for aging adults with an elevated risk of functional and cognitive decline. This K76 research proposal and parallel training plan will expand upon my expertise in motor control (gait) and signal processing (free-living gait) with neuropsychological assessment, advanced statistical methods, and aging systems biology (proteomics). Accomplishing the proposed training and research project will uniquely position me as a leader and expert in the intersection of physical function and systems biology, enabling me to lead the way in developing precision detection and treatment strategies in ADRD.
