Purpose Researchers aimed to determine whether chronic administration of a ketone monoester diet could improve anxiety and cognitive function and attenuate amyloid‑β (Aβ) and tau pathologies in the 3×TgAD mouse model. They also assessed whether ketone supplementation affects neuroinflammation and metabolic status. Methods Thirty male 3×TgAD mice were housed in groups and, at 8.5 months of age, randomly assigned to one of two diets: (1) a ketone ester diet containing D‑β‑hydroxybutyrate/R‑1,3‑butanediol (KET) providing ~21 % of calories as the ketone ester, or (2) a carbohydrate‑enriched control diet (CHO) with an isocaloric macronutrient composition but supplemented with sucrose. Animals were maintained on their diets until 12 and 15 months of age, when behavioural testing was conducted. Tests included open‑field locomotion, elevated plus‑maze for anxiety, and the Morris water maze for spatial learning and memory. At 16.5 months mice were euthanised; brains were sectioned and stained to quantify Aβ deposition, hyperphosphorylated tau, and microglial activation in hippocampal, amygdaloid and cortical regions. Plasma ketone and glucose concentrations were measured. Results Mice on the KET diet maintained lower body weight and exhibited higher circulating β‑hydroxybutyrate and lower glucose levels than CHO‑fed controls. Behaviourally, KET‑fed mice displayed greater exploratory locomotion and spent more time in the open arms of the elevated plus maze, indicating reduced anxiety. In the Morris water maze they learned the location of a hidden platform as quickly as age‑matched non‑transgenic mice and showed superior memory retention during probe trials compared with CHO‑fed 3×TgAD mice. Histological analysis revealed that KET diet markedly decreased Aβ deposits in the hippocampus, amygdala and cortex and reduced the number of AT8‑positive phospho‑tau inclusions. Microglial activation and inflammatory markers were also lower in KET‑fed brains. Collectively, these data show that chronic ketone ester supplementation preserves behavioural function and mitigates both amyloid and tau pathology in this AD model. Conclusion

A long‑term ketone ester diet improved anxiety and cognitive performance while reducing amyloid‑β and tau pathologies in 3×TgAD mice. The benefits were accompanied by reduced neuroinflammation and improved metabolic profiles, suggesting that sustained ketone elevation exerts neuroprotective effects. These findings support further investigation of ketone ester supplements or ketogenic diets as potential therapeutic strategies for Alzheimer’s disease and related cognitive disorders in humans.