Epidemiological evidence suggests that western-style diet and the resulting non-alcoholic fatty liver disease (NAFLD) negatively impact cognitive performance, yet this relationship had not been formally investigated in a mouse model. Presented at the 6th Global NASH Congress 2023 in London, this pilot study — developed in collaboration with Sylics and Novo Nordisk — investigated whether high-fat (HF) and high-fat, cholesterol, fructose (HFCF) diets impair cognitive performance in C57BL/6J mice following 20 weeks of feeding. 

Both HF and HFCF diets induced significant cognitive deficits compared to chow-fed controls — assessed via CognitionWall™ discrimination learning in automated PhenoTyper home-cages and the Morris Water Maze. These findings support the hypothesis that western-style diet predisposes to cognitive impairment and establish a translatable mouse model platform for testing therapeutics aimed at preventing or counteracting diet-induced cognitive deficits in the setting of metabolic disorders.

Epidemiological evidence suggests that increased consumption of western-style diet, leading to non-alcoholic fatty liver disease (NAFLD), has a negative impact on cognitive performance. However, the association between western-style diet and cognitive performance had not been thoroughly investigated in a mouse model. This pilot study investigated whether a western-style high-fat (HF) diet and a NAFLD-inducing diet — high fat with additional cholesterol and fructose (HFCF) — negatively impact cognitive performance. 

C57BL/6J mice aged 7–8 weeks were fed Chow (n=16), HF (D12492, n=16), or HFCF (D09100310, n=16) diet for 20 weeks. Following 20 weeks, mice were subjected to spatial learning and long-term reference memory assessment (Morris Water Maze) and cognitive discrimination and reversal learning (CognitionWall™ in PhenoTyper home-cages). 

Significant body weight increases were observed in both diet groups versus Chow controls. In the CognitionWall test, significant differences were detected among the survival curves (Gρ-weighted log-rank test, P<0.001), with both HF (P<0.001) and HFCF (P=0.002) mice showing deficits in reaching the learning criterion. In the Morris Water Maze, HF mice performed significantly worse than Chow mice in time spent in the platform quadrant after initial acquisition (P=0.019). In the 4-day reversal phase, HFCF mice performed significantly worse than Chow controls (P=0.023). 

Both HF and HFCF diets induced cognitive deficits in mice, supporting the hypothesis that western-style diet predisposes to cognitive impairment. These diets in combination with CognitionWall™ and Morris Water Maze constitute a valuable model platform for investigating the efficacy of treatments aimed at preventing and/or counteracting diet-induced cognitive deficits in the context of NAFLD and related metabolic disorders.