Allostatic load modifies neuropsychiatric risk following traumatic brain injury

Importance: Outcomes following traumatic brain injury (TBI) vary substantially, with a subset of individuals experiencing neuropsychiatric morbidity and worse prognosis. Exposure to psychosocial and environmental stressors may be an important, yet understudied, modifier of TBI trajectory. Allostatic load (AL) represents the cumulative physiological burden of chronic stress and provides a useful framework for evaluating pre-injury vulnerability. Objective: To assess the relationship between pre-injury AL burden and risk of mortality and incident neuropsychiatric diagnosis following TBI. Design, Setting, and Participants: This cohort study leveraged electronic health record, survey, and laboratory data from the All of Us Research Program, version 8. Participants aged 18 years or older enrolled between May 6, 2018, and October 1, 2023, were queried for TBI diagnosis using clinical diagnostic codes. Data were analyzed between November 11, 2024, and January 7, 2026. Exposure: The physiological burden of pre-injury chronic stress exposure was estimated using an AL index (pALI) derived from anthropometric and laboratory biomarkers collected before index TBI. Main Outcomes and Measures: Post-TBI mortality and incident neuropsychiatric diagnosis clusters. Mortality risk was assessed using Cox proportional hazards models (hazard ratio [HR] with 95% CI), and risk of incident neuropsychiatric diagnosis was modeled using competing-risk regression with death as a competing event (sub-distribution HR with 95% CI). Results: The primary cohort included 4,552 individuals with an established TBI diagnosis and sufficient biomarker data to estimate pALI. The pALI measure differed across sociodemographic groups and was positively correlated with perceived stress (r=.08, p=.002). Higher pALI was associated with increased post-TBI mortality risk (adjusted HR=1.71; 95%CI, 1.36-2.14). Elevated pALI was also associated with greater risk of incident post-traumatic stress disorder (PTSD; adjusted HR=1.28; 95%CI, 1.10-1.50) and sleep disorder (adjusted HR=1.42 95%CI, 1.29-1.57) diagnoses. Conclusions and Relevance: Higher pre-injury ALI was associated with increased risk of mortality and select neuropsychiatric outcomes following TBI, suggesting that AL burden may shape post-injury trajectories. Pre-injury chronic stress exposure and underlying stress biology may represent underrecognized determinants of vulnerability and resilience in brain injury recovery.