Background: Alzheimer’s disease (AD) is associated with plasma insulin elevations and reduced insulin efficiency, which may down-regulate transport of insulin to the brain and influence disease pathogenesis. Low CSF insulin levels have been observed in AD patients, and intravenous (IV) insulin administration (while maintaining euglycemia) improves memory, possibly by augmenting low brain levels. Peripherally administered insulin is not a viable treatment, however, due to the risk of hypoglycemia. After intranasal administration, insulin follows extracellular pathways to the brain and largely bypasses the periphery, directly accessing the CNS within 15 minutes and circumventing the risk of hypoglycemia. Objectives: We determined whether intranasal insulin facilitated cognition in a manner similar to IV administration. Methods: Subjects with early AD or amnestic mild cognitive impairment (MCI) were randomized to receive either placebo or intranasal insulin treatment (20 IU) twice daily using an electronic atomizer (ViaNase, Kurve Technology) for three weeks. Cognitive measures and blood were obtained at baseline, and after 10 and 21 days of treatment. Results: No changes were observed in plasma glucose or insulin levels with treatment. The treatment was well-tolerated, with no serious adverse events reported for any subject. The insulin-treated group showed enhanced ability to retain verbal information after a delay (memory savings) compared with the placebo-treated group (p=.03). Memory savings scores did not differ between the two groups at baseline, but were significantly higher in the insulin-treated group at day 21 [placebo group mean memory savings score with (SD)= 32 percent (26), insulin group mean=53 percent (13)]. The insulin-induced increase in memory savings was attenuated for older adults; change in memory savings was negatively correlated with age (–.97, p=.005) for the insulin treated group. For a subgroup of patients, insulin treatment modulated plasma beta amyloid and cortisol levels. Conclusions: These results support further study of the therapeutic benefits of intranasal administration.