INTRODUCTION: Intranasal (IN) insulin acutely improves verbal memory in mild cognitive impairment (MCI)/Alzheimer's disease (AD), but its therapeutic effects may be attenuated in apolipoprotein E4 (ApoE4) carriers. Furthermore, rapid-acting (RA) insulins may have superior therapeutic effects compared with regular insulin types. OBJECTIVES: To measure the safety and efficacy of intranasally delivered RA glulisine in ApoE4 carriers with mild-moderate AD. METHODS: We performed a double-blinded, randomized, cross-over study of RA insulin glulisine in nine mild-moderate AD subjects to better understand the relationship between RA insulin, ApoE4 carrier status and memory performance. RESULTS: IN glulisine was well tolerated but failed to have an acute impact on cognition in ApoE4 carriers with AD. Serum insulin levels acutely dropped following treatment, but peripheral glucose levels remained unchanged. CONCLUSION: Larger clinical trials of longer duration are necessary to better understand the relationships between RA insulin, ApoE4 carrier status and cognitive performance in AD.