Increased burden of endogenous viral elements in Alzheimer's Disease compared to cognitively healthy centenarians

INTRODUCTION: Throughout history, viruses have been infecting humans, leaving genomic traces called endogenous viral elements (EVEs). This study explores the infectious hypothesis for Alzheimer's disease (AD) that suggests that viral infections may contribute to AD by analyzing EVEs in genomes of AD patients and cognitively healthy centenarians (CHCs) measured by long-read sequencing. METHODS: We implemented an EVE detection pipeline that screened the genomes of 248 AD patients and 240 CHCs. EVEs were measured based on EVE count, length, and chromosome location. RESULTS: The genomes of AD patients contain significantly more EVEs than those of CHCs (p=3.2x10-4). Moreover, certain chromosomal regions in AD patients show a higher EVE count, particularly of the Orthoherpesviridae family, near genes differentially expressed in AD brains. DISCUSSION: These findings suggest that viral infections may increase susceptibility to AD, highlighting that preventive measures against infections potentially reduce AD risk.