OBJECTIVE While the apolipoprotein E e4 allele (ApoE-e4) is related to cognitive and brain decline in the general population, its effect on the brain in type 1 diabetes mellitus (T1DM) remains unclear. Therefore, the aim was to determine the interaction between ApoE-e4 and T1DM on cognitive performance and hippocampal struc-ture and connectivity as the brain area most vulnerable to ApoE-e4 effects in adult patients with T1DM. RESEARCH DESIGN AND METHODS Blood sampling was performed in 104 patients with T1DM and 49 control subjects for ApoE genotyping, neuropsychology, and neuroimaging to determine hip-pocampal volume and resting-state connectivity. The interaction between T1DM status and ApoE-e4 presence was investigated and adjusted for age and mean systolic blood pressure. RESULTS ApoE genotyping could not be performed for three patients with T1DM. Significant interaction effects, indicating a differential effect of ApoE-e4 between both groups, were found for overall cognitive functioning and for the subdomains of information processing speed and attention. Additionally, interaction effects were present for right hippocampal connectivity with the right posterior cingulate and supramarginal gyri. Subsequent group analysis showed that patients with T1DM with ApoE-e4 performed worse on these cognitive domains with increased connectivity, relative to their counterparts without ApoE-e4. In contrast, no cognitive effects, but decreased connectivity, were observed in control subjects with ApoE-e4. In patients with T1DM, higher right hippocampus connectivity with the posterior cingulate gyrus was related to poorer overall cognitive functioning. CONCLUSIONS The results may suggest that ApoE-e4 presence leaves our patients with T1DM more susceptible to cognitive decrements at a younger age, possibly through vascular pathways, warranting further longitudinal studies.