Sex differences in the IntelliCage and the Morris water maze in the APP/PS1 mouse model of amyloidosis

•Sex influences IntelliCage and Morris water maze performance outcomes.•Female mice perform worse in the Morris water maze.•Varied performance by APP/PS1 mice across memory tasks.•Aβ plaque load is higher in female versus male APP/PS1 mice.•Sex may override Aβ plaque load in predicting cognitive performance. Transgenic rodent models were created to decipher pathogenic mechanisms associated with Alzheimer's disease (AD), and behavioral apparatuses such as the Morris water maze (MWM) are used to assess cognition in mice. The IntelliCage was designed to circumvent issues of traditional behavioral tests, such as frequent human handling. The motivation to complete IntelliCage tasks is water consumption, which is less stressful than escaping from a pool in the MWM. Here, we examined behavioral performances of mice in the IntelliCage and MWM tasks. Twelve-month-old male and female APP/PS1 and non-transgenic mice first underwent 42 days of IntelliCage testing to assess prefrontal cortical and hippocampal function followed by MWM testing for six days. We found that females performed better in the IntelliCage while males performed superiorly in the MWM. Mechanistically, female APP/PS1 mice had a higher Amyloid-β plaque load throughout the brain, which is inconsistent with their performance in the IntelliCage. Collectively, these results inform scientists about the sex-based differences when testing animals in different behavioral paradigms that tap similar cognitive functions. [Display omitted]