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

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSThroughout history, viruses have been infecting humans, leaving genomic traces called endogenous viral elements (EVEs). This study explores the infectious hypothesis for Alzheimers 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. METHODSWe 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. RESULTSThe 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. DISCUSSIONThese findings suggest that viral infections may increase susceptibility to AD, highlighting that preventive measures against infections potentially reduce AD risk. Research in contextO_ST_ABSSystematic reviewC_ST_ABSAlzheimers disease (AD) is classically linked to {beta}-amyloid accumulation, but {beta}-amyloid may also act as an antimicrobial peptide against viruses like herpesvirus, supporting an infectious hypothesis where viral infection triggers {beta}-amyloid production. We tested this using endogenous viral elements via long-read sequencing in AD patients and cognitive healthy centenarians (CHC). InterpretationAD genomes carry significantly more endogenous viral elements than CHC genomes, with families including Orthoherpesviridae enriched at chromosomal regions near genes differentially expressed in AD brains and linked to a herpesvirus infection pathway. Future directionsOur computational analyses have identified novel human genetic loci that may influence Alzheimers disease pathology, opening new avenues for in vivo and in vitro investigations into its underlying mechanisms. Additionally, we emphasize the significance of endogenous viral elements in Alzheimers research and advocate for a global exploration of viral element heterogeneity to deepen our understanding of their potential role in disease progression. HighlightsO_LIFirst long-read screen for EVEs comparing AD patients and centenarians. C_LIO_LIAD genomes carry significantly more endogenous viral elements than CHCs. C_LIO_LIChr19 herpesvirus-enriched genes map to the Herpes Simplex Virus 1 pathway. C_LI