RD2 treatment of old-aged APP/PS1 mice resulted in significantly improved cognitive performance. Nesting behavior (a) and marble burying (b) were examined to investigate species-typical behavior. Neither RD2 nor placebo treatment had a significant influence on the nesting behavior, nor on the marble burying results, compared to non-transgenic littermates (ntg). An open field test was performed to analyze and compare the exploratory and anxiety-related behaviors of RD2- and placebo-treated mice, as well as their ntg (c, d). Mice were allowed to explore the arena, divided into border and center zones, for 25 min. Exploration of the center and border zones is represented as five different time slots (c). In contrast to placebo-treated mice, RD2-treated mice and ntg exhibited a habituation effect to the arena that significantly differs from the performance of placebo-treated mice (c). Analysis of overall exploration revealed a significant difference in the exploratory and anxiety-related behaviors between RD2- and placebo-treated mice but not between RD2-treated mice and ntg, indicating that RD2 treatment reversed the phenotype of the transgenic mice (d). Additionally, a Morris water maze (MWM) was conducted in which mice were trained for 5 days to find a hidden platform (e, f). Escape latencies to the platform of RD2-treated mice were significantly lower compared to placebo-treated mice, indicating improved learning, similar to ntg (e). In addition, RD2-treated mice and ntg spent significantly more time in the platform quadrant compared to placebo-treated mice on the last training day (f). Analysis of the probe trial revealed a significant difference between ntg and placebo-treated mice, but not between ntg and RD2-treated mice, respectively (g). Each behavioral performance of RD2-treated mice was similar to those of ntg, suggesting a reversed phenotype. Data is represented as mean ± SEM, RD2 n = 11, placebo n = 10, ntg n = 11