Transactive response DNA-binding protein 43 kDa (TDP-43) deposition is linked to regional brain atrophy in Alzheimer's disease (AD), but diffusion changes associated with AD-related TDP-43 proteinopathy remain underexplored. This study evaluates the potential of diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) as in vivo markers for detecting TDP-43 proteinopathy in AD. We analyzed DTI and NODDI metrics in 49 cases with AD neuropathologic changes, categorized by postmortem TDP-43 status. Diffusion metrics from the temporal lobe gray and white matter regions and key white matter tracts were compared between TDP-43-positive and negative cases. Group differences were significant in the left hippocampus, amygdala, and uncinate fasciculus after adjusting for age, Braak neurofibrillary tangle (NFT) stage and APOE ε4 status. TDP-43-positive cases showed increased mean diffusivity (MD) and altered neurite density index (NDI) and orientation dispersion index (ODI). Area under the receiver operating characteristic curve (AUROC) analysis revealed high predictive accuracy for amygdala ODI (AUC = 0.809, sensitivity = 0.81, specificity = 0.76), hippocampal MD (AUC = 0.763, sensitivity = 0.81, specificity = 0.67), and uncinate fasciculus MD (AUC = 0.782, sensitivity = 0.88, specificity = 0.61). Combined, DTI/NODDI predictors demonstrated stronger discriminative ability (AUC = 0.856, sensitivity = 0.88, specificity = 0.76). These findings suggest that AD-related TDP-43 proteinopathy is associated with specific diffusion changes in the left temporal lobe. DTI and NODDI metrics, particularly MD, NDI, and ODI, may improve the antemortem detection of TDP-43 pathology in AD.