Cumulative adverse childhood experiences increase migraine risk in later life in China: evidence from CHARLS with mediation and Mendelian randomization

BACKGROUND: Adverse Childhood Experiences (ACEs) are significant early-life stressors with long-term health impacts. Migraine is a prevalent, debilitating neurological disorder in middle-aged/elderly populations, often accompanied by depression. However, evidence on ACEs' influence on migraine risk in this demographic and the mediating role of depression is limited in Chinese populations. Using China Health and Retirement Longitudinal Study (CHARLS) data, the research investigated the connection of cumulative ACEs exposure with migraine risk in middle-aged/elderly individuals and examined depressive symptoms as a mediator. METHODS: 8,410 participants (≥ 45 years) from CHARLS (2011-2020) were analyzed. Standardized questionnaires assessed cumulative ACEs, migraine, and depressive symptoms. Multivariable COX regression analyzed the ACEs-migraine association. Bootstrap mediation analysis quantified depression's mediating role. Mendelian randomization (MR) was used for validation. RESULTS: After covariate adjustment, each additional ACE point increased migraine risk by 18% (HR = 1.18, 95% CI: 1.13-1.22, p < 0.001). Individuals with ≥ 4 ACEs had remarkably higher migraine risk compared to those with none (HR = 1.99, 95% CI: 1.64-2.41). Depressive symptoms significantly mediated 21.5% (95% CI: 16.3% - 29.0%, P < 0.01) of the connection of ACEs with migraine. ACEs increased migraine risk both directly and indirectly via heightened depressive symptoms. MR confirmed ACEs significantly increased migraine risk (IVW OR = 1.64, 95% CI: 1.20-2.22) and suggested depression mediated 20.1% (95% CI: 4.15% - 36.1%, P = 0.01) of the effect, supporting the primary findings. Genetic correlation between ACEs and migraine was significant (LDSC Rg = 0.23, P < 0.001). CONCLUSION: This study confirms cumulative ACEs exposure is a significant risk factor for migraine in middle-aged/elderly Chinese individuals. Depressive symptoms take a substantial mediating role. Findings indicate ACEs have complex effects on later-life neurological health, with depression acting as a key psychological mechanism linking early adversity to migraine.