Researchers at the University of Missouri have found that a high-fat, low-carbohydrate ketogenic diet improves gut bacteria and brain energy levels in female mice carrying the APOE4 gene, a major risk factor for Alzheimer's disease. The study highlights gender-specific effects, with males showing no similar benefits. These findings suggest potential for personalized nutrition to prevent cognitive decline.
Scientists at the University of Missouri are investigating how a ketogenic diet—high in fats from foods like fish, meat, non-starchy vegetables, berries, nuts, seeds, eggs, and full-fat dairy—might protect brain health, particularly for those genetically predisposed to Alzheimer's.
The research, led by Ai-Ling Lin, a professor in the School of Medicine, and doctoral student Kira Ivanich, focused on mice with the APOE4 gene, the strongest known genetic risk factor for late-onset Alzheimer's. In their study, female mice on the ketogenic diet developed healthier gut bacteria and exhibited higher brain energy levels compared to those on a high-carbohydrate diet. Male mice, however, did not show these improvements, indicating a gender influence on the diet's effects.
The brain's energy production is central to the findings. As Ivanich explained, "When we eat carbs, our brains convert the glucose into fuel for our brains, but those with the APOE4 gene—particularly females—struggle to convert the glucose into brain energy, and this can lead to cognitive decline down the road." She added, "By switching to a keto diet, ketones are produced and used as an alternative fuel source. This may decrease the chance of developing Alzheimer's by preserving the health of brain cells."
Lin emphasized the importance of precision nutrition, tailored to factors like genotype, gut microbiome, gender, and age. "Instead of expecting one solution to work for everyone, it might be better to consider a variety of factors," she said. "Since the symptoms of Alzheimer's—which tend to be irreversible once they start—usually appear after age 65, the time to be thinking about preserving brain health is well before then, so hopefully our research can offer hope to many people through early interventions."
Conducted at the Roy Blunt NextGen Precision Health building, the study benefits from the university's collaborative environment and advanced imaging facilities, enabling seamless transitions from animal models to potential human trials. For Ivanich, the work is personal: "When my grandmother got Alzheimer's, that sparked my interest in this topic, so being able to make an impact to help people preserve their brain health is very rewarding."
The paper, titled "Ketogenic diet modulates gut microbiota-brain metabolite axis in a sex-and genotype-specific manner in APOE4 mice," was published in the Journal of Neurochemistry in 2025.