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

Abstract

Background: Alternations in gut microbiota and a number of genes have been implicated as risk factors for the development of Alzheimer disease (AD). However, the interactions between the altered bacteria and risk genetic variants remain unclear.

Objective: We aimed to explore associations of the risk genetic variants with altered gut bacteria in the onset of AD.

Methods: We collected baseline data and stool and blood samples from 30 AD patients and 47 healthy controls in a case-control study. The rs42358/rs4512 (ApoE), rs3851179 (PICALM), rs744373 (BIN1), rs9331888 (CLU), rs670139 (MS4A4E), rs3764650 (ABCA7), rs3865444 (CD33), rs9349407 (CD2AP), rs11771145 (EPHA1), and rs3818361/rs6656401 (CR1) were sequenced, and microbiota composition was characterized using 16S rRNA gene sequencing. The associations of the altered gut bacteria with the risk genetics were analyzed.

Results: Apolipoprotein ε4 allele and rs744373 were risk loci for the AD among 12 genetic variants. Phylum Proteobacteria; orders Enterobacteriales, Deltaproteobacteria, and Desulfovibrionales; families Enterobacteriaceae and Desulfovibrionaceae; and genera Escherichia-Shigella, Ruminococcaceae_UCG_002, Shuttleworthia, Anaerofustis, Morganelia, Finegoldia, and Anaerotruncus were increased in AD subjects, whereas family Enterococcaceae and genera Megamonas, Enterococcus, and Anaerostipes were more abundant in controls (P < 0.05). Among the altered microbiota, APOE ε4 allele was positively associated with pathogens: Proteobacteria.

Conclusion: The interaction of APOE ε4 gene and the AD-promoting pathogens might be an important factor requiring for the promotion of AD. Targeting to microbiota might be an effective therapeutic strategy for AD susceptible to APOE ε4 allele. This needs further investigation.

Keywords: Alzheimer disease; apolipoprotein E; dysbiosis; genetic variants; gut microbiome.

FIGURE 1

Boxplots and statistical comparison (Wilcoxon rank-sum test) shows no significant difference between alpha diversities among groups including Sobs index (A) and Shannon index (B). P-values for each comparison are depicted above the boxplots of the groups being compared. Boxplot medians (center lines); interquartile ranges (box ranges). Patients with AD and healthy subjects are, respectively, colored in gray and rose red.

FIGURE 2

PCoA of bacterial beta diversity based on (A) Bray–Curtis dissimilarity, (B) Unweighted, and (C) Weighted UniFrac distances. Patients with Alzheimer disease and healthy subjects are, respectively, colored in gray and rose red and are indicated by circles.

FIGURE 3

Differences in the composition of gut microbiome between patients with AD and cognitive healthy subjects. Patients with Alzheimer disease and healthy subjects are, respectively, colored in gray and rose red. Gray bars and circles indicate significant.

FIGURE 4

Associations of AD associated genetic variants with specific members of the gut microbiota. The boxplots indicate the median (horizontal solid line) and the IQR between the first and third quartiles (box). ^∗indicate significance FDR < 0.05. A, Alzheimer disease; C, Cognitive healthy subjects.