Psychosocial stress in the first 25 years of life and cognitive function in midlife: the role of inflammation

Background
Early-life psychosocial stress (ELS) has lasting effects on physical and mental health, yet the biological mechanisms linking ELS to midlife cognitive function remain incompletely understood. Chronic, low-grade inflammation has been proposed as a key pathway, but prior studies have examined only a narrow set of markers.
Methods
We analyzed data from 326 participants (mean age = 39.4 years; 56.4% African American; 57.4% female) in two longitudinal cohorts with prospectively collected measures of psychosocial stress before age 25. Plasma concentrations of 1,034 proteins (including 537 inflammatory markers) were quantified using the Olink® Reveal platform. Cognitive function in midlife was assessed with the NIH Toolbox Cognition Battery. A composite ELS score integrated exposures across individual, family, and neighborhood domains. Weighted Quantile Sum (WQS) regression was used to estimate the joint effect of multiple proteins on cognitive function, adjusting for demographic and socioeconomic covariates.
Results
Higher ELS was significantly associated with poorer midlife cognitive performance (p = 0.008). Forty-five proteins were related to ELS (p < 0.01), with the strongest associations observed for CXCL17, ISM1, and ADM. Nine (e.g., LAMP3, SASH3, LPL, TNFRSF11A) out of these 45 proteins were associated with cognitive function, and their combined WQS index significantly mediated 35% of the ELS–cognition association (p = 0.013).ConclusionsThis study integrates prospective psychosocial, proteomic, and cognitive data to demonstrate that systemic inflammation partially mediates the long-term impact of early-life stress on midlife cognitive function. These findings highlight inflammation as a potential biological pathway linking early adversity to adult brain health.