Gut microbiome dysbiosis is linked to many neurological disorders including Alzheimer’s disease (AD). A major risk factor for AD is polymorphism in the apolipoprotein E (APOE) gene, which affects gut microbiome composition. To explore the gut-brain axis in AD, long-lived animal models of naturally developing AD-like pathologies are needed. The degu (Octodon degus) exhibits spontaneous AD-like symptoms and APOE mutations, making them suitable for studying the interplay between AD genetic determinants and gut microbiome. We analyzed the association between APOE genotype and gut microbiome in 50 humans and 32 degu using 16S rRNA gene amplicon sequencing. Significant associations were found between the degu APOE mutation and gut microbial changes, notably a depletion of Bacteroidetes and Firmicutes and an enrichment of Proteobacteria, mirroring patterns seen in people with AD. The altered taxa were previously suggested to be involved in AD, validating the degu as an unconventional model for studying the AD/microbiome crosstalk.