Microbiome alterations in Alzheimer's disease: A systematic review of current evidence and global perspectives

Abstract

Background Growing evidence implicates the gut–brain axis in Alzheimer's disease (AD), with gut microbiome dysbiosis proposed to modulate neuroinflammation, amyloid pathology, and cognitive decline. Objective To systematically synthesize human studies (2021–2025) profiling gut microbiomes in AD; identify consistent taxonomic and functional signatures; map geographic study distribution; and highlight translational gaps. Methods A PRISMA-compliant systematic review of human studies using 16S rRNA, metagenomics, metatranscriptomics, or fecal microbiota transplantation (FMT)/probiotic designs was conducted. Two reviewers screened studies and assessed quality using Joanna Briggs Institute tools. Owing to heterogeneity, findings were narratively synthesized across microbiome diversity, taxonomy, function, metabolism, oral–brain links, causality, interventions, and predictive analyses. Results Thirty-seven studies, mainly from Asia with some from Europe, North America, and Africa, revealed consistent gut dysbiosis in AD. Findings show reduced alpha-diversity, loss of short-chain fatty acid-producing bacteria (e.g., Faecalibacterium prausnitzii , Bifidobacterium ), and enrichment of pro-inflammatory taxa ( Escherichia/Shigella , Proteobacteria ). Functional analyses indicate reduced butyrate synthesis, disrupted lipid and tryptophan–kynurenine metabolism, and links with apolipoprotein epsilon (ε4) gene and cognition. Limited causal evidence arises from Mendelian randomization and small FMT trials, with randomized, longitudinal confirmation still needed. Conclusions Current evidence suggests a biologically plausible association between gut microbiota and AD pathogenesis, positioning microbiome-derived biomarkers and interventions as promising but still exploratory avenues. Harmonized, longitudinal, multi-omic, and geographically inclusive studies are urgently needed to clarify causal mechanisms and translate these correlational findings into validated diagnostics and therapeutics.