(P09-012-25) Abnormalities In Microbiome Contribute to Non-Responsiveness of Ketogenic Diet in Alzheimer’s Disease, and a Novel Synbiotics Formulation Ameliorates Them

Objectives: Ketogenic diet (KD) is beneficial for brain health by ameliorating cognitive impairments, including Alzheimer’s disease (AD); however, while many individuals respond well to KD intervention, many are nonresponsive. In this study, we tested a hypothesis that abnormalities in the microbiome contribute to the non-responsiveness of KD in older adults with mild cognitive impairment (MCI) to ameliorate AD pathology, and a synbiotic yogurt (SY) formulation reverses them.

Methods: We transplanted the microbiome of KD responders (RES) and non-responders (NRES) older adults with MCI to 3xTg mice and investigated whether the microbiome plays a causal role in KD responsiveness and, if so, then how. The animals were fed with KD supplemented with SY for four weeks.

Results: Our results indicated that mice that received NRES microbiome exhibited a significant increase in weight gain, while RES microbiome recipients retained normal weight despite consuming a higher amount of SY-supplemented diet. Further, NRES recipient mice showed higher impaired cognitive function and increased Aβ accumulation that are linked with reduced ketone body production, while RES recipients show no significant differences compared to non-treated controls. Interestingly, intervention with novel SY formulation significantly restored body weight gain, improved ketone body formation, and reduced Aβ pathology in NRES recipient mice. The SY effects were shown to reduce potentially harmful bacteria, Staphylococcus, while enriching beneficial bacteria, including Clostridium and Lactobacillus, and these effects were linked with reduced markers of gut permeability and systemic inflammation in NRES recipient mice compared to their controls.

Conclusions: This study highlights the critical role of the gut microbiome in modulating the responsiveness to KD effects in AD pathology. Intriguingly, KD combined with SY enhanced metabolic stability, ketone body production, and cognitive performance via beneficially modulating gut microbiome. These findings support a gut-microbiome-mediated mechanism underlying the therapeutic efficacy of KD in Alzheimer’s disease.

Funding Sources: We are grateful for funding support from Ed and Ethel Moore Alzheimer’s Disease Research Program, Florida Dept. of Health (22A17), and NIH, NIA (R56AG069676, R56AG064075, RF1AG071762, R21AG072379, U01AG076928).