Head injury/traumatic brain injury and the risk of dementia: An observational and Mendelian randomization study

This study aimed to investigate the link between head injury (HI)/traumatic brain injury (TBI) and dementia risk, as it remains unclear. We examined the associations between HI/TBI-related factors, including the frequency of HIs and the severity of TBI, and the risk of dementia ( n = 397,581), as well as neuroimaging outcomes ( n = 42,380) using prospective data (50 years at baseline) from the UK Biobank. In the observational analyses, Cox proportional-hazards modeling and logistic regression were used to estimate the associations between factors. Mendelian randomization (MR) was conducted to investigate the underlying causality between TBI ( n = 392,423, n cases =19,842) and Alzheimer's disease (AD) ( n = 41,944, n cases =21,982). During the 12.5-year follow-up period, 7524 participants developed dementia. HI and TBI conferred an increased dementia risk (hazard ratio (HR)=1.72, 95 % confidence interval (CI): 1.50–1.97; HR=1.86, 95 % CI: 1.46–2.38, respectively). The risk increased in relation to recurrent HIs (HR=4.05, 95 % CI: 2.24–7.32) or severe TBI (HR=4.50, 95 % CI: 3.18–6.37). Dementia risk was highest during the first 30 months following HI occurrence (HR=2.20, 95 % CI: 1.66–2.92), whereas there was no association after 40 years post-HI. Patients with recurrent HIs also exhibited reduced hippocampal volumes and increased white matter hyperintensity. HI was additionally associated with poorer reasoning ability and longer reaction time. Besides, the MR analysis supported a causal association between TBI and AD (odds ratio (OR)=1.17, 95 % CI: 1.01–1.37). These results imply that HI/TBI is associated with increased dementia risk. Strategies are needed to mitigate the impact of subsequent dementia.