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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has been characterized by gross cortical atrophy, cellular neurodegeneration, reactive gliosis, and the presence of microscopic extracellular amyloid plaques and intracellular neurofibrillary tangles. Earlier diagnoses of AD would be in the best interest of managing the patient and would allow for earlier therapeutic intervention. By measuring the apparent diffusion coefficient (ADC) using diffusion-weighted imaging (DWI), a type of magnetic resonance imaging (MRI), one can quantify alterations in water diffusivity resulting from microscopic structural changes in the cell at early stages that are associated with pathophysiological processes of brain injury and/or disease progression. Whether or not this methodology is useful for AD is a question under examination. For example, DWI in suspected AD patients has shown increases in mean ADC values in the hippocampus and diminished diffusion anisotropy in the posterior white matter. However, in some cases, hippocampal ADC values appear not to change in AD patients. Moreover, to our knowledge, all DWI studies in suspected AD patients to date are technically incomplete in experimental design, because corresponding histological sections demonstrating actual plaque deposition are lacking and so it is not clear that ADC changes actually correspond to plaque deposition. In our study, we used DWI in the TgCRND8 transgenic model of Alzheimer's disease in conjunction with histological techniques and found robust plaque deposition in the transgenic strain in older animals (12-16 months old). However, we did not find statistically significant changes (p > 0.05) in ADC values (although ADC values in TgCRND8 mice did decrease in all regions examined) in mice 12-16 months old. Collectively, recent results from human studies and in rodent AD transgenic models support our findings and suggest that amyloid beta plaque load is not likely the major or primary component contributing to diffusional changes, if they occur.