Abstract
Background
Multiple infectious agents, including viruses, bacteria, fungi, and protozoa, have been linked to Alzheimer disease (AD) by independent lines of evidence.
Method
We mapped and quantified DNA sequence reads from whole exome and whole genome sequencing data in 37,000 AD cases and controls from of the Alzheimer Disease Sequencing Project that did not align to the human genome to 318 viral reference sequences. After quality control, the sample included 1,696 samples derived from brain (cases=1,314, controls=382) and 14,588 derived from blood (cases=5,813, controls=8,775). We tested individual and cumulative normalized viral read counts, both free and inserted in the host genome, for association with AD using multiple machine learning (ML) classifiers, selecting the top 27 viral species according to an algorithm based on the species’ predictive rank weighted by the model’s overall predictive accuracy across models. These top 27 viruses were tested for association with AD using logistic regression models adjusted for PCR amplification, sequencing site, sex, APOE genotype, and ancestry. Analyses were stratified by tissue source.
Result
We detected sequence reads from 175 unique viral species, herpes simplex virus 1 (HSV‐1) being the most common. Viral read counts varied significantly by sequence center, tissue source, sex, PCR use, and ancestry in both the WES and WGS datasets. ML results indicated that herpes viruses (1, 2, 4, 5, 6A, 6B, 7, and 8), HIV, Hepatitis C, Molluscum contagiosum, several Torque Teno virus species (TTV), HPV‐71, Coronavirus 229E, Tick‐borne encephalitis, human Mastedenovirus, human polyomavirus 2, variola virus, primate t‐lymphotropic virus 1, human endogenous retrovirus K, and total normalized mapped viral reads were significant predictors of AD. Subsequent meta‐analyses of results stratified by tissue source showed that AD was significantly associated with HSV‐1(OR=4.07, P=2.22x10‐5), Human papillomavirus type 71(OR=3.26, P=0.006), TTV‐10 (OR=22.11, P=0.004) , and cumulative viral read count (OR=7.34, P=0.03). After multiple testing correction, HSV‐1 remains significant.
Conclusion
These results support the hypothesis that viral infections, especially HSV‐1, is associated with AD risk and demonstrate the potential of using deep sequencing technology to detect microbial agents in multiple tissues and discerning here‐to‐for unrecognized associations of infectious agents and AD.