Proteomic insights into childhood adversity: Exploring biological mechanisms and cognitive outcomes in the CARDIA...

Adverse childhood experiences (ACEs), including abuse, neglect, and household dysfunction, are among the most consequential adverse social experiences of early life and carry elevated risk of chronic disease and cognitive impairment in adulthood through biological pathways that are poorly understood. We examined the mediation of ACE-related plasma proteins, including immune signaling markers, in the association between childhood adversity and cognition in midlife using data from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Cognitive performance across verbal memory, processing speed, executive function, and global cognition was assessed with validated neuropsychological batteries. Among 2003 participants (mean [SD] age: 55 [3.6] years; 56% female; 42% Black), adjusted linear regression analyses showed that 35 proteins were significantly associated with at least one ACE (p < 0.001, a priori discovery threshold). Of these, two proteins were associated with cognition after adjusting for age, sex, race, and years of education, and correction for multiple comparisons (Benjamini-Hochberg false discovery rate [FDR], q < 0.05). Higher MCTS1, a regulator of translation re-initiation and cell cycle progression, was associated with worse processing speed (β = -0.088, q = 0.002), and higher AINX, a neuron-specific intermediate filament protein, was associated with worse executive function (β = -0.069, q = 0.025). Adjusted mediation analyses did not identify any significant pathways that may have explained the effects of ACEs on cognition. These findings suggest that ACEs are associated with alterations in specific circulating proteins, including MCTS1 and AINX, that are independently associated with cognitive performance in midlife. Although mediation analyses did not support these proteins as significant intermediaries association ACEs with cognition after correction for multiple comparisons, their convergent identification across independent analyses suggests they may be worth prioritizing as candidate biomarkers for future study.