AbstractThere is continuing debate about long-term effects of brain injury. We examined a range of traumatic brain injury (TBI) variables (TBI history, severity, frequency, and age of injury) as predictors of cognitive outcome over 8 years in an adult population, and interactions with apolipoprotein E (APOE) genotype, sex, and age cohorts. Three randomly sampled age cohorts (20–24, 40–44, 60–64 years at baseline; N = 6333) were each evaluated three times over 8 years. TBI variables, based on self-report, were separately modeled as predictors of cognitive performance using linear mixed effects models. TBI predicted longitudinal cognitive decline in all three age groups. APOE ε4⁺ genotypes in the young and middle-aged groups predicted lower baseline cognitive performance in the context of TBI. Baseline cognitive performance was better for young females than males but this pattern reversed in middle age and old age. The findings suggest TBI history is associated with long-term cognitive impairment and decline across the adult lifespan. A role for APOE genotype was apparent in the younger cohorts but there was no evidence that it is associated with impairment in early old age. The effect of sex and TBI on cognition varied with age cohort, consistent with a proposed neuroprotective role for estrogen. (JINS, 2014, 20, 444–454)