Background Chronic inflammation contributes to neurodegeneration and cerebrovascular injury, yet it remains unclear whether inflammatory biomarkers influence white matter hyperintensity (WMH) volume and cognition independent of Alzheimer's disease (AD) plasma biomarkers. Objective This study examined whether inflammatory biomarkers were associated with WMH volume and multidomain cognitive performance independent of AD plasma biomarkers, and whether WMH volume mediated associations between IL-6 and cognition. Methods Using data from 1806 participants in the Health and Aging Brain Study–Health Disparities (HABS-HD), we examined associations between log transformed plasma inflammatory biomarkers (IL-10, TNF-α, IL-6, and IL-5) and WMH volume and cognitive performance (memory, executive function, processing speed, language). Multivariable linear regression models adjusted for demographic and vascular risk factors were repeated with additional adjustment for AD biomarkers (p-Tau181, NfL, total tau, Aβ 42/40 ). Mediation analyses were included to test whether WMH meditated the association between IL-6 and cognitive domains. Results Higher IL-6 levels were consistently associated with increased WMH volume in base and AD-adjusted regression models. Increased levels of IL-6 were also associated with poorer performance in all cognitive domains, but these associations did not survive multiple comparisons correction. WMH partially mediated the association between IL-6 and memory (23%) and processing speed (19%). Conclusions Elevated IL-6 is independently linked to cerebrovascular injury and poorer cognition beyond classical AD biomarkers, supporting a vascular–inflammatory pathway distinct from amyloid and tau pathology. These findings underscore the importance of integrating inflammatory and neurodegenerative markers to elucidate heterogeneous mechanisms of brain aging across diverse populations.
Dharmapuri et al. (Wed,) studied this question.