To measure the effect of rapid acting (RA) intranasal (IN) insulin on global cognition and function in mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD).

IN insulin is a potential treatment for neurodegenerative disease shown to reduce amyloid plaques and improve verbal memory in memory-impaired adults.  Investigations have suggested that rapid-acting (RA) insulins such as glulisine may result in superior cognitive benefits compared to regular insulin.

A single center, randomized, double-blind, placebo-controlled study was performed to test the efficacy of IN glulisine versus placebo in N=35 MCI/AD subjects.   IN administration utilized the Impel NeuroPharma I109 Precision Olfactory Delivery (POD®) device.  The ADAS-Cog13, CDR global score, and FAQ were measured at baseline, 3 and 6 months.  Secondary outcome measures included digit span forward/backwards, Trailmaking part A/B, COWAT, and WMS logical memory.  Depression and suicidality were assessed using GDS and C-SSRS.

No significant differences in education, ApoE4 status, and MOCA score existed between treatment groups.  Overall, the number of adverse events per person was similar between groups (2.32 vs. 2.24, p=0.824); although subjects receiving IN glulisine had higher rates of nasal irritation (25.0% vs 13.9%) and respiratory symptoms (15.9% vs 8.3%) compared to placebo.  Glucose<70 was observed in one subject receiving RA insulin, but otherwise, there were no other cases of hypoglycemia, including three NIDDM patients.  No significant difference for ADAS-Cog 13, CDR or FAQ scores were found between treatment groups at 3 and 6 months. 

IN glulisine was safe and well-tolerated and did not consistently impact peripheral glucose.  There were no enhancing effects of IN glulisine on cognition, function, or mood, but the ability to detect significances was limited by number of subjects successfully enrolled and study duration.  Additional investigations following a larger MCI/AD cohort over a longer duration are necessary to better evaluate RA insulin efficacy in this population.