Bostick, J. W.; Connerly, T. J.; Thron, T.; Needham, B. D.; de Castro Fonseca, M.; Kaddurah-Daouk, R.; Knight, R.; Mazmanian, S. K.

INTRODUCTION: Preclinical studies reveal that the microbiome broadly affects immune responses and the deposition and/or clearance of amyloid-beta 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.