Abstract INTRODUCTION Preclinical studies reveal that the microbiome broadly affects immune responses and the deposition and/or clearance of amyloid-beta (Aβ) in mouse models of Alzheimer’s disease (AD). Whether the microbiome shapes central and peripheral immune profiles in AD models remains unknown. METHODS We examined adaptive immune responses in two mouse models containing AD-related genetic predispositions (3xTg and 5xFAD) in the presence or absence of the microbiome. RESULTS T and B cells were altered in brain-associated and systemic immune tissues between genetic models and wildtype mice, with earlier signs if inflammation in female mice. Systemic immune responses were modulated by the microbiome and differed by sex. Further, the absence of a microbiome in germ-free mice resulted in reduced cognitive deficits, primarily in female mice. DISCUSSION These data reveal sexual dimorphism in early signs of inflammation and the effects of the microbiome, and highlight a previously unrecognized interaction between sex and the microbiome in mouse models of AD. Research in Context Systemic review: We reviewed the literature related to Alzheimer’s disease (AD), inflammation, and the microbiome using PubMed. We cite several studies that demonstrate the influence of the microbiome on inflammation and cognitive performance in both animal models and humans. However, the mechanisms linking immunity to AD are not well understood. Interpretation: Using two well-established mouse models of AD, we found that the microbiome does not strongly influence the onset of inflammation in brain-draining lymph nodes; rather, it largely modulates systemic immune responses, local cytokine production, and cognitive performance. Notably, the inflammatory state in mice was affected by sex, and this sex effect differed between local and systemic tissues and mice with or without a microbiome. Future directions: Our work identified a sex- and microbiome-mediated effect on inflammation and cognitive performance. Future studies may focus on microbiome-dependent mechanisms that intersect with sex hormone and immune responses to determine peripheral effects on AD outcomes. Highlights Adaptive immunity is activated at early ages and differentially by sex in mouse models of AD. Inflammation in 5xFAD mice is characterized by increased IL-17A-producing T cells. Inflammation in 3xTg mice is characterized by increased cytokine responses in males, but attenuated cytokine responses in female mice. Longitudinal immune responses differ between 3xTg mice and 5xFAD mice. Both 3xTg and 5xFAD female mice show improved learning and cognition in the absence of a microbiome.

The microbiome shapes immunity in a sex-specific manner in mouse models of Alzheimer’s disease