Differential associations of plasma biomarkers with Alzheimer's disease and small vessel disease: A multimodal imaging study

Abstract

INTRODUCTION: We investigated how plasma biomarkers (phosphorylated tau 217 [ptau217], glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) relate to imaging markers of small vessel disease (SVD) and Alzheimer's disease (AD), and cognition in memory clinic patients. METHODS: 76 memory clinic patients underwent plasma biomarker assessment, neuropsychological testing, and 3T MRI. SVD burden was assessed using white matter hyperintensity (WMH) volume, mean skeletonized mean diffusivity (MSMD), and fiber density. AD-related neurodegeneration was captured by AD-signature cortical thickness and fiber-bundle cross-section. Findings were validated in 41 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants with amyloid-/tau-positron emission tomography (PET). RESULTS: Associations varied between biomarkers. NfL showed strongest associations with SVD burden, ptau217 with AD-related neurodegeneration, while GFAP was linked to both. SVD markers were associated with processing speed, whereas AD markers were most associated with memory. DISCUSSION: NfL relates to SVD burden, while ptau217 remains most sensitive to AD-related biomarkers. GFAP's dual associations suggest overlapping biological processes. Together, coexisting SVD should be considered when interpreting plasma biomarkers in memory clinic patients.