APOE-ε4 Carrier Status and Gut Microbiota Dysbiosis in Patients With Alzheimer Disease Original paper

What was studied?

This original research article investigated APOE-ε4 gut microbiota dysbiosis as a mechanistic link between Alzheimer’s disease (AD) genetic susceptibility and intestinal microbial alterations. The researchers aimed to determine whether known AD-related genetic variants—particularly the APOE ε4 allele—corresponded to specific shifts in gut bacterial composition. Using a case–control design, they sequenced 16S rRNA profiles from fecal samples and conducted genotyping across twelve AD-associated SNPs. The study explored whether APOE-ε4 status influenced microbial abundance patterns characteristic of AD, focusing on pathogen-enriched taxa such as Proteobacteria and beneficial short-chain-fatty-acid–producing genera.

Who was studied?

The study involved 30 clinically diagnosed AD patients and 47 cognitively healthy, age- and sex-matched controls recruited from Xinjin, Chengdu, China. After exclusion criteria related to antibiotic use, diet, gastrointestinal disorders, and comorbidities, stool samples suitable for microbiota analysis were obtained from 21 AD participants and 40 controls. All individuals were older adults aged 60–80 years. The population was ethnically homogeneous, reducing confounding from dietary and cultural variability. Genetic profiles were generated from fasting blood samples, and APOE genotypes were derived from rs7412 and rs429358 alleles.

Most important findings

The study demonstrated clear AD-associated microbial signatures. AD patients showed increased Proteobacteria, Enterobacteriales, Deltaproteobacteria, Desulfovibrionales, Enterobacteriaceae, and Desulfovibrionaceae, with notable enrichment of Escherichia–Shigella, Ruminococcaceae, Shuttleworthia, Morganelia, Finegoldia, and Anaerotruncus. Controls instead exhibited higher levels of Enterococcaceae, Megamonas, Enterococcus, and Anaerostipes—genera associated with short-chain-fatty-acid (SCFA) production such as butyrate. Importantly, APOE ε4 carriage showed a strong positive association with the abundance of Proteobacteria and Enterococcaceae, independent of AD status. BIN1 rs744373 was also associated with AD risk, though microbial correlations centered primarily on APOE ε4. These findings align with the concept that APOE ε4 predisposes individuals to dysbiosis characterized by pro-inflammatory, pathogen-rich taxa and reduced SCFA-producing microbes.

Key implications

The findings suggest that APOE-ε4 gut microbiota dysbiosis may amplify AD risk by promoting microbial communities enriched in Proteobacteria and related pathogens while depleting metabolically beneficial SCFA-producing species. This genetic–microbial interaction strengthens the hypothesis that AD pathogenesis involves peripheral microbial signals and barrier dysfunction. Therapeutic strategies aimed at restoring microbial homeostasis—particularly enhancing SCFA-producing taxa such as Megamonas, Enterococcus, and Anaerostipes—may benefit genetically susceptible APOE ε4 carriers. The study reinforces microbiome-genotype interactions as a promising domain for precision-based AD interventions.

Citation

Hou M, Xu G, Ran M, Luo W, Wang H. APOE-ε4 carrier status and gut microbiota dysbiosis in patients with Alzheimer disease. Frontiers in Neuroscience. 2021;15:619051. doi:10.3389/fnins.2021.619051