Abstract Body: Introduction
Traumatic brain injury (TBI) is a recognized risk factor for late-onset dementia (LOD), though its specific association with early-onset dementia (EOD) (i.e., diagnosed before age 65) is less understood. This study examines the association between TBI, and the risk of developing EOD compared to LOD through a population-based cohort study. Additionally, a systematic review with meta-analysis examines the association between TBI and EOD.

Hypothesis
TBI is a risk factor for developing EOD and this association between TBI and EOD is stronger than the association with LOD.

Methods
We utilized data from 502,039 participants aged 40 - 69 years at recruitment from the UK Biobank and found that 16,959 people had TBI. Over a median follow-up of 13.6 years, 837 people were diagnosed with EOD, and 8948 with LOD. We estimated hazard ratios (HRs) for TBI's association with EOD and LOD using Cox proportional hazard models with TBI modeled as both a time-varying exposure and time-varying coefficient. Additionally, we conducted a systematic review of existing studies of TBI and EOD, with pooled effect estimates generated via a random-effects model.

Results
TBI was significantly associated with an increased risk of both EOD (HR: 3.3, 95% CI: 2.5-4.5) and LOD (HR: 2.5, 95% CI: 2.3-2.7). The association was stronger for EOD compared to LOD (p-value: 0.05), especially in the case of moderate to severe TBI (p-value: 0.15) (Figure 1). A meta-analysis including 10 studies and the present study using UK Biobank, estimated a pooled effect estimate of 1.9 (95% CI: 1.2-3.0), with effect estimates ranging from 0.7 to 5.4, for EOD associated with TBI, albeit with high heterogeneity (I² = 96%).

Conclusion
This study underscores that TBI is associated with an increased risk of EOD, more so than LOD. These findings emphasize the need for targeted preventive strategies and interventions for individuals with a history of TBI to mitigate or delay dementia onset.