Muscle quality & memory: The role of inflammation and white matter in the muscle-brain axis - PROJECT SUMMARY Sarcopenia, an age-related decline in muscle mass and strength, affects 26% of individuals with neurodegener-ative diseases like Alzheimer's disease (AD). Sarcopenia and AD share biological pathways, including systerric inflammation and impaired brain white matter integrity (WMl)-that may contribute to a decline in episodic memory, the hallmark cognitive symptom of AD. These overlapping pathways highlight the interrelation of muscle quality and brain health-termed the muscle-brain axis. While prior studies have linked poor muscle quality to global WMI deficits (e.g., white matter hyperintensity burden) and episodic memory impairment, WMI in trac1s key for episodic memory like the fornix and hippocampal cingulum (CGH) have not been examined in this con-text. Moreover, interleukin-6 (IL6), a pro-inflammatory cytokine, is negatively associated with fomix WMI, yet its association with CGH WMI is unclear. It is also unknown whether growth differentiation factor-15 (GDF15), an-other cytokine implicated in muscle quality and brain health decline, is related to WMI in either tract. Preliminary data from our lab support the muscle-brain axis link, yet no study has joinUy examined muscle quality, inflamma-tion, WMI, and episodic memory within an integrated framework. Furthermore, unlike prior studies using handgrip strength alone, this study will use a more robust measure of muscle quality: knee extensor strength relative to thigh muscle mass. Systemic inflammation will be assessed using both established (IL6) and emerging (GDF15) biomarkers linked to poor muscle quality and neurodegeneration. WMI of the fornix and CGH will be assessed using diffusion tensor imaging. This integrative approach will help establish evidence for a mechanistic chain underlying the muscle-brain axis, positioning muscle quality as a modffiable risk factor for neurodegenerative disease. My central hypothesis is that muscle quality is positively associated with episodic memory performance, and this relationship is mediated by inflammatory markers and WMI. Although the cross-sectional design pre-cludes formal mediation testing, it provides proof-of-concept and is achievable within the F31 mechanism. The aims are to: 1) Evaluate the extent to which muscle quality and inflammatory marker levels independently predict episodic memory and the degree to which the explained variance is shared between, versus unique to, each predictor; 2) Evaluate the extent to which muscle quality and WMI independenUy predict episodic memory and the degree to which the explained variance is shared between, versus unique to, each predictor; and 3) Evaluate the extentto which inflammatory marker levels predict WMI. By integrating muscle quality, inflammatory markers, and tract-specific WMI within a unified analytic framework, this study will clarify their contribution to episodic memory variance and provide novel insights into physiological pathways through which the muscle-brain axis functions. As an F31 fellowship, this project will provide rigorous training in muscular physiology, blood-based biomarker analysis, neuroimaging. and neuropsychological assessment-preparing the applicant for an inde-pendent research career focused on lifestyle-related risk and resilience in neurodegenerative disease.
