The validity of the diagnosis, i.e. sensitivity, specificity and accuracy, cannot be assessed. To overcome this misclassification bias, we restricted our inclusion to patients who were registered in the CIC or those prescribed with medications solely for dementia, as there should be impossible for false positive cases on this side of disease spectrum. Epidemiologic study showed the prevalence of dementia in the elderly in Taiwan ranged from 1.7% to 4.4%, which is similar with our sampled data. The prevalence in 5-year age bands from 65 to 84 years, and for those aged 85 years and older was 0.41%, 0.82%, 1.62%, 2.55% and 4.0%, respectively. Although frequencies were lower compared with the global report published by Cleusa et al, the upward trends were the same. We acknowledged that dementia patients with mild symptoms would not be enrolled and this approach decreases the generalizability of study findings, but we had decided this a must trade-off. Second, Coding errors are also common in mTBI. In Bazarian et al., the sensitivity of ICD-9-CM codes for mTBI was 45.9% with a specificity of 97.8%. In other words, people in the mTBI group are highly possible to have mTBI, while some people in the unexposed group may still have mTBI during the study period but the inclusion strategy failed to identify them. In this situation, the predicted effect of mTBI on dementia should be toward the null, but we still found AbMole Brusatol significant risk of developing dementia in patients with mTBI. Third, we could not obtain the clinical information of patients with mTBI, such as the Glasgow Coma Scale, findings on computed tomography of head, the injury mechanism and the initial presentations. By definition, labeling our cases as ��mTBI�� may be inappropriate. However, it has been validated that the ICD9-CM codes have high specificity regarding diagnosis of mTBI. Furthermore, we excluded those who were admitted to the hospitals to make sure the patients enrolled are really “mild”. Based on our inclusion criteria, although not totally precise, we think the cases in our study group are highly correlated with the definition of mTBI. Fourth, the average duration from TBI to the diagnosis of dementia is short and we admitted that reverse causation might also exist. However, we excluded all dementia patients in the first 3 years of our study period to eliminate the effect as possible. Of note, patients in TBI group are older; it is possible the neurodegenerative impact after TBI could have stronger effect on the elderly. Furthermore, we found higher HR of dementia in patients admitted with TBI and the reverse causation could not fully explain the ��doseresponse�� of injury severity. In the last, although we extensively adjust for possible comorbidities, unmeasured cofounding is still an issue. Based on the nature of our dataset, we cannot take some important risk factors of dementia such as gene or family histories into account. However, these risk factors are unlikely associated with mTBI and it is reasonable that these are not confounders in our study. Furthermore, the adjusted HR is significant enough that the residual confounding may not be able to fully explain the result. Studies have found a history of head trauma was associated with increase in the risk for AD in the absence of a family history of dementia. In Plassman et al, 548 World War II veterans hospitalized during military service between 1944 and 1945 with a diagnosis of nonpenetrating TBI were compared with 1228 patients matched on education and age. A history of severe and moderate TBI increased the risk of dementia, but there was no significant risk of dementia in those with mTBI. In our study, we further extend 
the impact of TBI to the mild type, utilizing the largest cohort study to date to identify that patients with single mTBI have higher risk of developing dementia later in their lives compared to general population.