A Metagenomic Study of Gut Viral Markers in Amyloid-Positive Alzheimer’s Disease Patients

Abstract Background Mounting evidence suggests the involvement of viruses in the development and treatment of Alzheimer’s disease (AD). However, there remains a significant research gap in metagenomic studies investigating the gut virome of AD patients, leaving gut viral dysbiosis in AD unexplored. This study aimed to fill this gap by conducting a metagenomics analysis of the gut virome in both amyloid-positive AD patients (Aβ + ADs) and healthy controls (HCs), with the objective of identifying viral signatures linked with AD. Method Whole-genome sequence (WGS) data from 65 human participants, including 30 Aβ + ADs and 35 HCs, was obtained from the database NCBI SRA (Bio Project: PRJEB47976). The Metaphlan3 pipeline and linear discriminant analysis effect size (LEfSe) analysis were utilized for the bioinformatics process and the detection of viral signatures, respectively. In addition, the Benjamini–Hochberg method was applied with a significance cutoff of 0.05 to evaluate the false discovery rate for all biomarkers identified by LEfSe. The CombiROC model was employed to determine the discriminatory power of the viral signatures identified by LEfSe. Results Compared to HCs, the gut virome profiles of Aβ + ADs showed lower alpha diversity, indicating a lower bacteriophage richness. The Siphoviridae family was decreased in Aβ + ADs. Significant decreases of Lactococcus phages were found in Aβ + ADs, including bIL285, Lactococcus phage bIL286, Lactococcus phage bIL309, and Lactococcus phage BK5 T, Lactococcus phage BM13, Lactococcus phage P335 sensu lato, Lactococcus phage phiLC3, Lactococcus phage r1t, Lactococcus phage Tuc2009, Lactococcus phage ul36, and Lactococcus virus bIL67. The predictive combined model of these viral signatures obtained an area under the curve of 0.958 when discriminating Aβ + ADs from HCs. Conclusion This is the first study to identify distinct viral signatures in the intestine that can be used to effectively distinguish individuals with AD from HCs.