Studies in mouse models of Alzheimer disease (AD) have revealed that perturbations of the gut microbiota can affect the deposition of amyloid-β (Aβ) — a peptide widely implicated in AD pathophysiology. However, no studies have shown that such perturbations affect tau-mediated neurodegeneration, another feature of this disease. Now, Seo et al. find that disruption of the gut microbiota affects neuronal loss in a mouse model of tauopathy and that this effect is dependent on expression of apolipoprotein E4 (APOE4).