Women are twice as likely as men to develop Alzheimer’s disease, particularly in later life. While hormonal differences between biological sexes have been suggested as a potential explanation for this disparity, the exact reasons remain unclear. Recently, the gut microbiome has emerged as a key area of interest in Alzheimer’s research due to its role in disease progression and observed differences between males and females. Since gut microbiome alterations appear early in Alzheimer’s development, we aim to investigate whether gut microbial composition and their metabolites could influence sex-specific Alzheimer’s pathologies, such as birth of new neurons, glial cell responses, and amyloid-β (Aβ) plaque accumulation—a hallmark of Alzheimer’s.

Alzheimer’s mouse models, such as the 5xFAD, mirror the sex differences seen in humans, with female mice developing more plaques than males of the same age. To explore potential links between gut microbiota and Alzheimer’s pathology, we will conduct a gut microbiome transfer experiment, transplanting gut bacteria from male to female 5xFAD mice and vice versa. This will help determine whether the gut microbiota can alter Alzheimer’s -related pathologies and behavioral outcomes in recipients to resemble those found in the donor. Additionally, since various brain cells respond to gut-derived metabolites, we will use cell culture studies to examine whether serum metabolites from male or female 5xFAD mice differentially affect neuronal growth or microglial Aβ uptake. By integrating these findings, we hope to identify specific gut microbes contributing to sex differences in Alzheimer’s and better understand the gut-brain axis in Alzheimer’s progression