Diffusion-weighted imaging (DWI) holds the promise of detecting very subtle neuronal changes in Alzheimer’s disease (AD). We compare the sensitivity of different DWI metrics to microstructural change in a transgenic rat model of AD. We find genotype-related differences in regions known to be affected in AD, with NODDI metrics showing greater sensitivity than FA and MD. However, no genotype-related difference in neuronal density is detected using immunohistochemistry staining for NeuN suggesting that the DWI changes reflect alterations in the neuronal structure (dendritic density or myelination) rather than density. DWI metrics are however correlated with neuronal density on a regional basis.