REGIONAL VULNERABILITY OF WHITE MATTER MICROSTRUCTURE IN EARLY ALZHEIMER’S DISEASE: EVIDENCE FROM 5XFAD MICE

Alzheimer’s disease (AD) causes progressive cognitive decline and is classically linked to gray matter pathology, yet evidence indicates that white matter alterations can appear early. Myelin disruption may contribute to network dysfunction within hippocampal pathways, including the corpus callosum and the fimbria. Here, diffusion magnetic resonance imaging (dMRI) was used to characterize in vivo microstructural white matter changes in the 5xFAD transgenic mouse model of familial AD, alongside early behavioral readouts of cognitive performance.
Male and female wild-type and 5xFAD mice were evaluated starting at 2 months of age and followed until 6 months of age. dMRI was performed to assess white matter microstructure, while cognitive function was examined using the Y-maze spontaneous alternation task. Diffusion tensor imaging (DTI) metrics, including fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AxD), and apparent diffusion coefficient (ADC), were extracted from predefined regions of interest within the frontal, medial, and caudal corpus callosum, the fimbria, and the hippocampus.
RD analysis revealed region- and age-dependent alterations, with the corpus callosum showing mild genotype differences and heterogeneous vulnerability across its subregions. The fimbria exhibited subtle increases in RD in 5xFAD mice, suggesting early disruption of hippocampal connectivity pathways, whereas the hippocampus showed high variability. FA displayed modest reductions in 5xFAD mice, while AxD and ADC showed no genotype differences, supporting the interpretation of early myelin-related rather than axonal alterations. Behaviorally, spontaneous alternation performance in the Y-maze revealed significant main effects of age, sex, and genotype, indicating early functional impairments in 5xFAD mice.