Allostatic load modifies neuropsychiatric risk following traumatic brain injury
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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.
KEY POINTS
Question
Is the physiological burden of chronic stress, estimated by allostatic load (AL), associated with worse outcomes following traumatic brain injury (TBI)?
Findings
Among 4,552 All of Us participants with TBI, higher pre-injury AL was associated with increased mortality risk and greater incidence of post-traumatic stress disorder and sleep disorder diagnosis following injury.
Meaning:
These findings suggest that the cumulative physiological burden of chronic stress may be an underrecognized modifier of TBI recovery and outcomes that could inform brain trauma risk stratification and prognostication.
