medRxiv · Apr 18, 2026
Herpes simplex virus type 1 DNA is less prevalent in persons with Alzheimer’s disease and genetic factors modify the effect
By Tejeda M, Farrell JJ, Zhu C et al.
INTRODUCTION Herpes simplex virus-1 (HSV-1) has been implicated in Alzheimer disease (AD). METHODS Reads from Alzheimer’s Disease Sequencing Project whole-genome sequencing data collected from brain (2,203 AD; 616 controls) and blood (8,908 AD; 15,768 controls) were aligned to viral genomes. Generalized linear mixed-models tested for the effect of HSV-1 DNA on AD, and we performed GWAS on HSV-1 presence and SNP×HSV-1 interaction effects on AD, adjusting for age, sex, tissue, library preparation, relatedness, and ancestry principal components. RESULTS Across ancestry groups, HSV-1 DNA was consistently less frequent in AD cases; reads predominantly mapped to regions containing the latency-associated transcript region. DNA prevalence was lower in APOE -ε4 carriers; HSV-1 was associated with reduced AD risk in ε4 non-carriers but increased risk in carriers. GWAS identified host genetic influences on HSV-1 detection and interaction loci affecting AD risk. DISCUSSION HSV-1 DNA showed an inverse association with AD and is affected by genetics.