AbstractBackgroundTo explore whether the age at onset (AAO) of Chinese patients with moyamoya disease (MMD) increased over time due to a reduced exposure to leptospiral infection.MethodsWe performed an independent, multicenter, retrospective study based on data from patients with MMD who initially attended four tertiary hospitals in Hubei, China, from 1996 to 2020. After stratifying the year of MMD onset into five periods (1996–2000, 2001–2005, 2006–2010, 2011–2015, and 2016–2020), we analyzed the temporal trends in AAO and compared different classes of AAO (early‐onset, < 20 years; intermediate‐onset, 20–49 years; late‐onset, ≥ 50 years) in each period.ResultsWe included 1858 patients in this study, with 878 women and 980 men. Their median (IQR) AAO was 47 (39‒55) years. The case AAO significantly increased at the rate of 0.94 years per year (r= 0.406,p< .0001), while no trend was observed in birth years through time (p= .512). The birth cohorts who grew up in the leptospirosis epidemic years was stably susceptible to MMD. The median (IQR) AAO has increased significantly from 26 (14–37) years (1996–2000) to 51 (43–57) years (2016–2020) (p< .0001). The proportion of early‐onset MMD was significantly higher in 1996–2000 (33.3%,p< .0001) and 2001–2005 (10.4%,p< .001). The AAO shows an aging trend that the proportion of late‐onset MMD went from 4.5% (2001–2005) to 54.5% (2016–2020) (p< .0001).ConclusionsThe AAO of MMD was increasing during a recent 25‐year period in China, which may reflect a birth cohort effect that resulted from environmental changes. The disparity risk of birth cohorts with MMD changed with leptospirosis epidemics, suggesting leptospiral exposure might be a potential risk factor.