Objective:This study aims to identify clinicopathological factors contributing to mild cognitive impairment (MCI) reversion to normal cognition.Methods:We analyzed three longitudinal cohorts in this study, including Mayo Clinic Study of Aging (MCSA), the Religious Orders Study and Memory and Aging Project (ROSMAP), and the National Alzheimer’s Coordinating Center (NACC). The demographic characteristics and clinical outcomes were compared between MCI subjects with or without an experience of reversion to normal cognition (referred to as reverters and non-reverters, respectively). We also compared longitudinal changes in cortical thickness, glucose metabolism, amyloid and tau load in a sub-cohort of reverters and non-reverters in MCSA with MRI or PET imaging information from multiple visits.ResultsWe identified 164 (56.4%) individuals in MCSA, 508 (66.8%) individuals in ROSMAP, and 280 (34.1%) individuals in NACC who experienced MCI reversion to normal cognition. Cox proportional hazards regression models showed that MCI reverters had an increased chance of being cognitively normal at the last visit in MCSA (HR, 3.31; 95% CI, 2.14 to 5.12), ROSMAP (HR, 3.72; 95% CI, 2.50 to 5.56), and NACC (HR, 9.29; 95% CI, 6.45 to 13.40) and a reduced risk of progression to dementia (HR, 0.12; 95% CI, 0.05 to 0.29 in MCSA; HR, 0.41; 95% CI, 0.32 to 0.53 in ROSMAP and HR, 0.29; 95% CI, 0.21 to 0.40 in NACC). Compared to MCI non-reverters, reverters had better-preserved cortical thickness (β = 0.082, P < 0.001) and glucose metabolism (β = 0.119, P = 0.001) and lower levels of amyloid, albeit, statistically non-significant (β = -0.172, P = 0.090). However, no difference in tau load was found between reverters and non-reverters (β = 0.073, P = 0.24).Conclusion:MCI reversion to normal cognition is likely attributed to the better-preserved cortical structure and glucose metabolism.