Diet-Dependent Cognitive Benefits of Exogenous Ketone Body Precursor, (R,S)-1,3,-Butanediol, in a Mouse Model of Tauopathy

Alzheimer’s disease and related tauopathies are escalating public health threats, particularly in the context of obesity and metabolic dysfunction, which accelerate cerebral glucose hypometabolism, tau pathology, neurodegeneration, and cognitive decline. Ketogenic therapies reconfigure systemic fuel metabolism, with emerging evidence for neuroprotection. (R,S)-1,3-butanediol (BD) raises circulating D- and L-β-hydroxybutyrate (βOHB) concentrations. To evaluate whether BD improves cognitive function across dietary contexts, male and female tau-transgenic mice and littermate controls received 10% BD in drinking water for 20 or 30 weeks starting at 6 weeks of age. BD rapidly induced ketosis (1.5-3.0 mM βOHB) in chow-fed mice, with L-βOHB contributing to ∼75% of the circulating βOHB pool. Despite minimal effects of BD on body weight and glucose homeostasis, and no effect on histopathological tau signal, 20-week BD treatment improved memory to control levels in chow-fed female tauopathy mice. Isotope-tracing untargeted metabolomics revealed that BD-treatment differentially affected glucose-derived ¹³ C-enrichment of metabolites in brains of male and female mice. BD-induced cognitive benefits in tau-transgenic mice were abrogated when mice were maintained on BD for 30 weeks on standard chow or when mice were administered BD over 20 weeks while maintained on a high-fat, Western diet, Notably, BD-induced ketosis was blunted in mice consuming Western diet. Moreover, intermittent ketogenic diet-induced ketosis failed to improve cognition in Western diet-fed tauopathy mice. These results suggest BD-induced ketosis extends cognitive benefits in a manner dependent on biological sex and nutritional metabolic status. Taken together, these data contextualize the roles of βOHB as modulators of cognitive resilience in tauopathy.