Preclinical Alzheimer’s disease is associated with distinct gut microbial metagenomic profiles
Year: 2023
Type: article
Abstract: Background Alterations in gut microbiome in individuals with Alzheimer’s disease (AD) may contribute to development or exacerbation of AD pathology via the microbiota‐gut‐brain axis. Composition and diversity of gut microbiota have been studied previously in AD dementia; here we investigate the gut microbial genes involved and their association with AD pathology prior to development of dementia. Method Cerebrospinal fluid (CSF; N = 98) and fecal samples (N = 333) were collected from participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center studies. CSF biomarkers of AD, β‐amyloid (Aβ)42/Aβ40 and phosphorylated‐tau‐181 (phospho‐tau [181P]), were quantified using robust prototype assays from the Roche NeuroToolKit (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Fecal samples were analyzed by whole genome sequencing. Sequences were filtered, quality controlled, and profiled for taxonomy and functional classification at species level using MetaPhlAn 4.0/HUMAnN 3.0 software. Compositional/functional differential abundance, alpha‐/beta‐diversity, correlation between feature abundance and sample metadata, gene‐set enrichment (GSE), and network analyses were performed using R packages (phyloseq/vegan/DESeq2/NetCoMi/rstatix/clusterProfiler). Analyses compared clinical status and biomarker groups. Result The relative abundance of phylum Firmicutes and Bacteroidetes decreased and increased, respectively, in individuals with AD versus cognitively unimpaired (CU) individuals. In CU individuals, functional profiles differed in Aβ‐positive (A+) and phospho‐tau [181P]‐positive (T+) groups versus Aβ‐ and phospho‐tau [181P]‐negative (A−T−) individuals. In the microbial metagenome, 64 genes were significantly increased (p < 0.05) in the A+T+ group versus the A−T− group; 21/64 genes had ≥1 significant correlation with the AD biomarkers (e.g., toxic protein SymE positively correlated with phospho‐tau [181P] and negatively correlated with Aβ42/Aβ40 in CU individuals, suggesting that it may be a contributor to pathophysiological metabolic pathways in AD). Three KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways identified in GSE analyses, including fatty acid metabolism/degradation and cationic antimicrobial peptide resistance, were significantly associated (p < 0.05) with genes that were enriched in the AD population versus CU individuals. Conclusion Individuals with AD have distinct differential abundance in microbiota composition, in addition to an increase and enrichment of genes associated with AD pathogenesis pathways. These genes were associated with AD biomarkers prior to development of AD dementia.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.073847
Authors: Jea Woo Kang, Margo B. Heston, Yuetiva Deming, Antonio González, Tyler K. Ulland, Sterling C Johnson, Sanjay Asthana, Cynthia M. Carlsson, Nathaniel A. Chin, Ethan Grover, Vaibhav BV Vemuganti, Gwendlyn Kollmorgen, Margherita Carboni, Kaj Blennow, Henrik Zetterberg, Rob Knight, Rima F. Kaddurah‐Daouk, Federico E. Rey, Barbara B Bendlin
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4390199043