Genotype and microbiome shape immunity in a sex-specific manner in mouse models of Alzheimer’s disease

Preclinical studies have revealed that the microbiome broadly affects immune responses and deposition and/or clearance of amyloid-beta (Aβ) in mouse models of Alzheimer’s disease (AD), but whether, and how, the microbiome shapes central and peripheral immune profiles in AD models remains unknown. 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 to determine if it promotes dysregulated immune responses and cognition in AD. T and B cells were altered in central nervous system (CNS)-associated lymph nodes and systemic immune tissues between genetic models and wildtype mice, with earlier signs of heightened immune activity in females. Systemic immune responses were modulated by the microbiome and differed by sex. Further, the absence of a microbiome in germ-free mice resulted in increased cognitive deficits, primarily in males. These data reveal sexual dimorphism in early signs of immune activity and microbiome effects, and highlight how sex and the microbiome shape responses in mouse models of AD.