U-shaped pattern in the association between serum magnesium levels and long-term dementia risk after traumatic brain injury: a retrospective cohort study

Abstract

Background In the general population, abnormal serum magnesium levels are associated with an increased risk of cognitive decline and dementia. However, whether this association extends to patients with traumatic brain injury (TBI), a population with distinct neurobiological vulnerabilities, remains unknown. Methods Using the TriNetX Global Collaborative Network, we identified adults aged ≥50 years with a history of intracranial injury (ICD-10-CM: S06). Patients with repeatedly low serum magnesium levels (< 1.7 mg/dL, two measurements within 1 year) were compared with those with normal levels (1.70–2.20 mg/dL) using 1:1 propensity score matching. A 1-year landmark period was applied to reduce the reverse causation. The primary outcome was incident dementia over 10 years of follow-up. The secondary outcomes included dementia subtypes, cognitive dysfunction, and all-cause mortality. To explore a potential U-shaped relationship, a parallel analysis was conducted comparing patients with repeatedly high magnesium levels (>2.20 mg/dL) with the same reference cohort. Sensitivity analyses, subgroup analyses by sex and TBI severity, and multivariable Cox regression were performed. Results After matching, 11,716 patients were retained in each cohort. Low magnesium levels were associated with a higher 10-year risk of incident dementia [2.53% vs. 1.78%; hazard ratio (HR) 1.62, 95% confidence interval (CI), 1.36–1.94; p < 0.001]. Among the secondary outcomes, associations were observed for vascular dementia (HR 1.97, p = 0.001), other dementia types (HR 1.63, p < 0.001), cognitive dysfunction (HR 1.43, p = 0.009), and all-cause mortality (HR 1.29, p < 0.001), whereas Alzheimer's disease did not reach significance (HR 1.43, p = 0.075). High magnesium levels were similarly associated with an increased risk of dementia (HR 1.57, p < 0.001). The findings were consistent across sensitivity and subgroup analyses and after multivariable adjustment (adjusted HR 1.50, p < 0.001). Conclusion In adults with prior TBI, both low and high serum magnesium levels were associated with a greater long-term risk of dementia, suggesting a U-shaped relationship. Prospective studies are needed to determine whether monitoring or modifying magnesium status can alter the post-traumatic dementia trajectory.