Frailty and Brain Myelin Across Adulthood: Multimodal <scp>MRI</scp> Insights From the <scp>BLSA</scp>

Frailty is a state of reduced physiological resilience and increased vulnerability to adverse health outcomes, but its neurobiological mechanisms across the adult lifespan remain unclear. Emerging evidence suggests that white matter (WM) alterations may accompany frailty, but previous neuroimaging studies have focused mostly on older adults and used nonspecific MRI markers. This study investigates whether systemic frailty, quantified using a Frailty Index (FI), is associated with WM myelin content and integrity using advanced quantitative MRI. A total of 88 participants (aged 22-94 years, mean = 59.9 ± 20.0) from the Baltimore Longitudinal Study of Aging underwent multicomponent relaxometry MRI to measure myelin content, as well as relaxation rates R1 and R2 to probe white matter overall integrity. Multiple linear regression models examined the relationship between FI and whole-brain and regional MRI biomarkers, adjusting for age and sex. Principal component analysis was used to explore global patterns of myelin and microstructural variation. Higher frailty scores were significantly associated with lower MWF across nearly all WM regions, especially in long-range tracts such as the corona radiata and corpus callosum. R1 and R2 also showed inverse associations with FI, suggesting broader white matter vulnerability. These findings provide the initial evidence linking frailty to brain myelin alterations across the adult lifespan. The study highlights myelin degradation as a candidate neural substrate of frailty and underscores the importance of advanced quantitative MRI in detecting early brain vulnerability related to frailty. Further research is needed to clarify the causal relationship between frailty and myelin changes.