Richard E. Brown

The 5xFAD mouse model of Alzheimer's disease (AD) rapidly develops AD‐related neuro‐behavioral pathology. Learning and memory impairments in 5xFAD mice, however, are not always replicated and the size of impairments varies considerably across studies. To examine possible sources of this variability, we analyzed the effects of age, sex, albinism due to background genes ( Tyr c , Oca2 p ) and motor impairment on learning and memory performance of wild type and 5xFAD mice on the Morris water maze, from 3 to 15 months of age. The 5xFAD mice showed impaired learning at 6–9 months of age, but memory impairments were not detected with the test procedure used in this study. Performance of 5xFAD mice was profoundly impaired at 12–15 months of age, but was accompanied by slower swim speeds than wild‐type mice and a frequent failure to locate the escape platform. Overall female mice performed worse than males, and reversal learning impairments in 5xFAD mice were more pronounced in females than males. Albino mice performed worse than pigmented mice, confirming that albinism can impair performance of 5xFAD mice independently of AD‐related transgenes. Overall, these results show that 5xFAD mice have impaired learning performance at 6–9 months of age, but learning and memory performance at 12–15 months is confounded with motor impairments. Furthermore, sex and albinism should be controlled to provide an accurate assessment of AD‐related transgenes on learning and memory. These results will help reduce variability across pre‐clinical experiments with 5xFAD mice, and thus enhance the reliability of studies developing new therapeutics for AD.