Background : The mechanisms underlying the protective effect of the e2 variant of the APOE gene (APOEe2) against Alzheimer’s disease (AD) have not been elucidated. We altered the microbiota of 3xTgAD mice by fecal microbiota transplantation from a human APOEe2 donor (e2-FMT) and tested the effect of microbiota perturbations on brain AD pathology.

Methods : FMT of bacteria isolated from stools of untreated 3xTgAD mice (M-FMT) or e2-FMT were transplanted in 15-month-old 3xTgAD mice. FMT was done alone or in combination with antibiotic and proton-pump inhibitor following the Microbiota Transfer Therapy protocol (MTT). The effect of donor (M or e2) and transplantation protocol (FMT or MTT) on hippocampal amyloid, tau pathology and neuroinflammation were assessed at the end of the treatment.

Results : e2-FMT reduced amyloid, and tau pathology as well as increased neuroinflammation as compared with M-FMT. MTT was associated with reduced number of Aβ40+ plaques and tau pathology. Low levels of amyloid were associated with high levels of pro-inflammatory molecules in e2-FMT mice. These associations were partially attenuated by MTT.

Conclusion : Bacteria from a human APOEe2 donor reduced AD pathology and increased neuroinflammation in mice suggesting that the gut microbiota may be a mediator of the protective effect of APOEe2.