Association of Fractional Anisotropy in White Matter Bundles with Plasma Biomarkers of Neurodegeneration and Glial Reactivity in Individuals with Cognitive Complaints without dementia

Age-related cognitive decline is preceded by subtle neurochemical and structural brain alterations that remain insufficiently characterized, particularly in individuals with cognitive complaints but without dementia. Circulating plasma biomarkers reflecting amyloid pathology, tau phosphorylation, astroglial reactivity, and axonal injury have emerged as accessible indicators of early neurodegenerative processes; however, their relationship with early white matter microstructural changes remains unclear. In this study, we investigated associations between plasma Aβ42/Aβ40, phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), and white matter integrity assessed by fractional anisotropy (FA) derived from diffusion MRI. We analyzed data from 135 community-dwelling older adults with cognitive complaints but without dementia, recruited through a population-based strategy. Diffusion MRI data were processed using deterministic and correlational tractography to identify white matter pathways in which FA was significantly associated with plasma biomarker levels, controlling for age and education. Anatomical labeling of implicated tracts was performed using probabilistic white matter atlases. Higher plasma levels of p-tau217 and GFAP were consistently associated with reduced FA across multiple periventricular white matter tracts, including the corpus callosum, fornix, optic radiations, and posterior thalamic radiations—pathways known to be vulnerable in early cognitive impairment. NfL exhibited a similar but more spatially restricted pattern, primarily involving callosal fibers. In parallel, direct associations between plasma biomarker levels and increased FA were observed in limbic-related bundles such as the cingulum and fornix, suggesting regionally specific microstructural responses that may reflect early adaptive or remodeling processes. Together, these findings demonstrate that plasma biomarkers of neurodegeneration and glial reactivity are closely linked to white matter microstructural alterations at pre-dementia stages. This study provides converging neurochemical and neuroanatomical evidence supporting the utility of blood-based biomarkers as indicators of early brain structural vulnerability and reinforces their translational relevance in the study of age-related neurodegenerative processes.