Early-life Varicella Infection and Long-term Protective Associations with Chronic Disease Risk: A UK Biobank Cohort Study *

A bstract The long-term impact of early-life varicella infection on chronic disease risk remains understudied. In this UK Biobank analysis, we found that documented early-life varicella infection was associated with significantly reduced risks of multiple chronic diseases, with the strongest protective associations for neurodegenerative conditions (Alzheimer’s disease: HR = 0.23, Parkinson’s disease: HR = 0.46). These inverse associations were consistently stronger in women, increased with age, and remarkably, appeared to outweigh the effects of socioeconomic deprivation on disease risk. Mendelian randomization analyses supported causality for several outcomes. Prior varicella infection was further associated with favorable baseline health profiles, including lower BMI, improved lung function, and reduced inflammatory markers. Our findings suggest that early-life varicella infection may confer long-term protection against chronic diseases through persistent modulation of immune and inflammatory pathways, challenging simplified views of infections as uniformly harmful and highlighting the complex, time-dependent interactions between infectious exposures and chronic disease risk across the lifespan.