Abstract A093: 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 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 neurological conditions were excluded. We assessed three MRI markers of cSVD: white matter hyperintensities (WMH), 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. Results: Among 5,270 participants (mean age 54.2±7.8 years; 53.4% female), higher baseline GFAP levels were significantly associated with all three MRI cSVD markers: WMH volume ( β = 0.06, 95% CI: 0.01-0.10, p = 0.014), FA ( β = 0.08, 95% CI: 0.03-0.13, p = 0.001), and MD ( β = 0.14, 95% CI: 0.09-0.18, p < 0.001) after 9 years. In 1,317 participants with longitudinal MRI data, baseline GFAP was associated with progression of FA ( β = 0.012, 95% CI: 0.001-0.023, p = 0.033) and MD ( β = 0.020, 95% CI: 0.003-0.038, p = 0.025) over 3 years. NfL was not significantly associated with any MRI cSVD marker. Longitudinal changes in biomarkers were not associated with concurrent MRI changes. 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 for cSVD, enabling preventive strategies when interventions may be most effective.