Adverse experiences in childhood and young adulthood, genetic susceptibility, and neurodegenerative disease incidence: a lifespan analysis

<b>Background:</b> Much remains unknown about the associations between adverse childhood experiences (ACEs), adverse adulthood experiences (AAEs) and the risk of neurodegenerative diseases, including dementia and Parkinson's disease (PD).<b>Purpose:</b> To examine the associations of ACEs and AAEs with incident dementia and PD, and to evaluate their interactions with genetic risk.<b>Methods:</b> We included 147,942 participants (mean [SD]: 55.9 [7.7] years) without dementia and PD at baseline from UK Biobank. ACEs and AAEs were assessed through an online mental health questionnaire, including emotional neglect, physical abuse, emotional abuse, sexual abuse, and physical neglect. Polygenic risk scores (PRS) were constructed for dementia and PD. Replication analysis was conducted in the China Health and Retirement Longitudinal Study (CHARLS) cohort.<b>Results:</b> During a median follow-up of 15.1 years, 851 incident dementia and 729 PD cases occurred. A greater number of ACEs was associated with increased risks of dementia (HR, 1.14, 95% CI: 1.08-1.21, per additional ACE) and PD (1.11, 1.04-1.18). Similarly, a higher number of AAEs was linked to elevated risks of dementia (1.16, 1.09-1.24) and PD (1.02, 0.95-1.10), though the latter was not statistically significant. Moreover, significant additive interactions between ACEs, AAEs, and genetic risk were observed for dementia, which accounted for an additional 13% to 19% of dementia cases. Results from the CHARLS confirmed the associations of ACEs and AAEs with dementia and PD.<b>Conclusions:</b> Exposure to ACEs or AAEs was associated with increased risks of dementia and PD. The dementia risk associated with ACEs was amplified in individuals with AAEs or high genetic susceptibility. These findings highlight the importance of life-course prevention targeting both ACEs and AAEs in mitigating dementia and PD risks, particularly among individuals with high genetic susceptibility. These findings should be interpreted with caution due to potential recall bias, self-reported assessments, and selection bias.