Multiple viruses detected in human DNA are associated with Alzheimer disease risk.

Abstract

Multiple infectious agents, including viruses, bacteria, fungi, and protozoa, have been linked to Alzheimer disease (AD) by independent lines of evidence. We quantified DNA sequence reads that align to viral and bacterial reference sequences present in whole exome (WES, N= 15,125) and whole genome (WGS, N= 4,443) sequences measured in blood (N=17,817) and brain (N=1,751) tissue from non-Hispanic white, African American and Caribbean Hispanic participants of the AD Sequencing Project including 9,380 AD cases and 10,188 controls. We tested the association of individual and cumulative normalized viral read counts with AD using logistic and LASSO regression models adjusting for tissue source, sequencing site, sex, APOE genotype, and population. Additional models were tested in subsets stratified by WES/WGS and tissue source. We used PathSeq, a software tool that performs subtraction on high-throughput sequencing data, to identify inserted microbial DNA and tested those species for association with AD. We detected sequences from 175 unique species of human viruses and 17,219 bacteria. Many individual and the cumulative viral read counts varied significantly by sequence center, tissue source, sex, and ancestry. Cumulative normalized human viral read count was associated with AD in every subset of the data (ORmeta = 1.05 per 100,000 units, Pmeta < 7.81x10-12 ). In the WES dataset, the presence of inserted herpes virus 6A sequence measured by PathSeq was protective against AD (OR=0.41, P=0.0007). We also found significant associations using LASSO. In the WES dataset, Hepatitis C was associated with increased AD risk. Herpes 6B was associated with decreased AD risk in both the WES and WGS datasets. In brain samples, herpes 4 and 6B were negatively associated with AD in both WES and WGS datasets, whereas herpes 8 was positively associated with AD and human herpes 3 was negatively associated in the WES dataset. No bacterial species were significantly associated with AD. These results are consistent with the hypothesis that viral infections contribute to AD pathogenesis and highlight the utility of next generation sequencing to detect microbial agents in multiple tissues. Contrary to previous results, except for human herpes 8, herpes viral DNA species are protective against AD.