Association of Plasma GFAP and NfL in Middle-Aged Adults With MRI Markers of Cerebral Small Vessel Disease Later in Life

BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (cSVD) is a major contributor to stroke and dementia, often beginning decades before clinical symptoms appear. While MRI markers offer critical insight into cSVD burden, blood-based biomarkers may offer a more accessible complement to neuroimaging. We investigated whether plasma glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are associated with MRI markers of cSVD in middle-aged adults and whether they are associated with longitudinal progression. METHODS: We conducted a retrospective analysis of prospectively collected data from the UK Biobank cohort. Participants aged 40-60 years at baseline (2006-2010) with plasma biomarker measurements and follow-up MRI scans (2014-2019) were included. Individuals with prevalent neurologic conditions were excluded. We assessed 3 MRI markers of cSVD: white matter hyperintensities (WMHs), fractional anisotropy (FA), and mean diffusivity (MD). Three analytical approaches were used: associations between baseline biomarkers and future MRI markers, associations between baseline biomarkers and longitudinal MRI changes, and correlations between longitudinal biomarker and MRI changes. Robust regression models were adjusted for age, sex, and cerebrovascular risk factors. RESULTS: = 0.025) over 3 years. NfL was not significantly associated with any MRI cSVD marker. Longitudinal changes in both biomarkers showed no significant associations with concurrent MRI progression. DISCUSSION: Plasma GFAP levels were associated with subsequent changes in white matter integrity among middle-aged adults, suggesting potential utility as an early indicator of cSVD vulnerability. These associations, observed nearly a decade after biomarker measurement, highlight GFAP's potential for long-term risk stratification. Blood-based biomarkers may support earlier identification of individuals at heightened risk of cSVD, enabling preventive strategies when interventions may be most effective.