Structural and diffusion MRI (dMRI) analyses can be used to characterize neurodegeneration during Alzheimer’s disease progression. Male and female mice with a targeted replacement of mouse APOE gene with humanized APOEε3 or APOEε4, underwent behavioral, transcriptomic and imaging analyses. Postmortem MRI of fixed brains included high resolution T2-weighted and diffusion weighted imaging. Structural volume assessment revealed that APOE genotype and sex have a significant impact on regional brain volumes. dMRI quantified white matter microstructural differences between APOEε3 or APOEε4 females/males which maybe cross-validated with transcriptomic and behavioral findings. Further confirmation of microstructural assessment is pending by electron micrographs.