Conflicting findings exist regarding the formation of diffuse and dense-core β-amyloid (Aβ) plaques in Alzheimer's disease (AD). In the present study, we characterized Aβ plaque types in the brain and spinal cord of TgCRND8 mice, which express a transgene incorporating both the Indiana mutation (V717F) and the Swedish mutations (K670N/M671L) in the human amyloid-β protein precursor (APP) gene. By combining immunohistochemistry and thioflavin S staining, we were able to define dense-core and diffuse plaques in neocortex of the brain and spinal cord of 9 week-, 5 month-, 10 month- and 20-month-old TgCRND8 mice. The senile plaques in the neocortex were predominantly dense-core plaques, even in the youngest mice. However, diffuse plaques were instead detected in spinal cord of the mice, regardless of age. Our results that relative predominance of dense-core plaques in the neocortex and diffuse plaques in the spinal cord of TgCNRD8 mice of all disease durations argue against the notion that diffuse plaques may represent an early stage in the evolution of dense-core plaques. Furthermore, we also found that the ratio of Aβ42/Aβ40 of the brain was much higher than that of the spinal cord by Aβ ELISA assay. Our findings strongly indicate that diffuse and dense-core plaques may form via independent processes in AD and Aβ42 is more prone to form dense-core plaques than is Aβ40.