Analysis of whole-genome sequencing data from 27,495 individuals reveals HSV-1 DNA appears less frequently in Alzheimer's disease patients compared to controls, with viral reads primarily mapping to latency-associated transcript regions in brain and blood samples. The effect varied significantly by APOE genotype: HSV-1 associated with reduced Alzheimer's risk in APOE-ε4 non-carriers but increased risk in carriers. This finding challenges the prevailing hypothesis that HSV-1 contributes to Alzheimer's pathogenesis. The inverse association could reflect compromised viral reactivation in diseased brains, altered immune surveillance, or differential viral clearance mechanisms. However, the cross-sectional design cannot establish whether reduced HSV-1 detection precedes or follows neurodegeneration. The APOE interaction suggests personalized risk profiles may be crucial for understanding viral contributions to dementia. While this large-scale genomic approach provides robust statistical power, the methodology detecting viral DNA rather than active infection limits mechanistic interpretation. As a preprint awaiting peer review, these counterintuitive results require validation through longitudinal studies tracking viral load changes during disease progression before reshaping our understanding of infectious agents in Alzheimer's disease.