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

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.