Abstract Body (Do not enter title and authors here): Background
Adverse Childhood Experiences (ACEs) have profound effects on physical and mental health across the lifespan. However, how ACEs influence the co-occurrence and progression patterns between cardiometabolic diseases (CMDs) and depression remains poorly understood. This study aimed to investigate ACE-related disease progression patterns and evaluate the effect modification of genetic predisposition and lifestyle factors.

Method
This study was conducted on a prospective cohort study of 203,449 UK Biobank participants who were free of CMDs and depression at baseline and had complete ACE data. ACEs, including emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect, were assessed, with cumulative ACE scores (range 0-5) categorized as low (0), intermediate (1-2), or high (≥3) exposure. Outcomes included incident CMDs (a composite of type 2 diabetes, coronary artery disease, stroke, and heart failure), depression, their multimorbidity, and mortality. Disease trajectories and transitions were analyzed using multistate models. Both additive and multiplicative interactions of genetic predisposition and healthy lifestyle with ACE exposure were investigated to assess their modification effects.

Result
During a median follow-up of 14.8 years, 5859 individuals developed CMD only, 6523 developed depression only, and 1507 developed multimorbidity of CMD and depression. ACE exposure showed dose-response associations with risk of CMD-depression multimorbidity (HRs: 1.07-3.89), with stronger associations observed for depression-related trajectories (HRs: 1.19-3.89) than CMD-related trajectories (HRs: 1.07-3.61). The probability of progressing from depression to multimorbidity (12.8-15.5%) was significantly higher than that from CMD to multimorbidity (4.5-7.2%) across three ACE groups. Emotional abuse showed the strongest associations with depression-related trajectories. High genetic predisposition amplified ACE-associated risks (up to 8.51-fold for the depression-CMD transition), while healthy lifestyle attenuated 30.4-93.2% of the ACE-associated risks.

Conclusion
This study underscores the dose-response effect of ACEs on CMD-depression multimorbidity, revealing transition-specific vulnerability to early-life adversity. The findings that genetic predisposition amplifies, while healthy lifestyle attenuates ACE-associated risks, suggest opportunities for targeted intervention strategies.