Larger clinical trials of longer duration are necessary to better understand the relationships between RA insulin, ApoE4 carrier status and cognitive performance in AD.

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Background Individuals with Down syndrome are likely to develop clinical and neuropathological brain changes resembling Alzheimer's disease dementia by the ages of 35-40 years. Intranasal insulin is a potential treatment for neurodegenerative disease that has been shown to reduce amyloid plaque burden and improve verbal memory performance in normal as well as memory-impaired adults. Investigations have shown that rapid-acting insulins may result in superior cognitive benefits compared with regular insulin. Objectives The primary objective of this study was to measure the safety and feasibility of intranasal rapid-acting glulisine in subjects with Down syndrome. Secondarily, we estimated the effects of intranasal glulisine on cognition and memory in Down syndrome. Methods A single-center, single-dose, randomized, double-blind, placebo-controlled, cross-over pilot study was performed to test the safety of intranasal glulisine vs placebo in 12 subjects with Down syndrome aged ≥ 35 years. Intranasal administration utilized the Impel NeuroPharma I109 Precision Olfactory Delivery (POD ®) device. The primary outcomes were the occurrence of any or related adverse and serious adverse events. Secondary post-treatment cognitive outcome measures included performance on the Fuld Object-Memory Evaluation and Rivermead Behavioral Memory Test. Results Intranasal glulisine was safe and well tolerated in the Down syndrome population. No adverse or serious adverse events were observed. Conclusions Further investigations are necessary to better evaluate the potential cognitive-enhancing role of intranasal insulin in the Down syndrome population. ClinicalTrials.gov ID NCT02432716.

Background IN insulin is a potential treatment for neurodegenerative disease shown to increase cerebral glucose update, reduce amyloid plaques and improve verbal memory in cognitively‐impaired as well as normal adults. Investigations have suggested that rapid‐acting (RA) insulins such as glulisine may result in superior cognitive benefits compared to regular insulin. Method We performed a single center, randomized, double‐blind, placebo‐controlled study to evaluate the efficacy of IN glulisine versus placebo in N=35 memory impaired (MCI/AD) subjects. Subjects with non‐insulin dependent diabetes mellitus (NIDDM) were included in the study. 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 the GDS and C‐SSRS Results Subjects in the saline group were significantly older than those in the saline group (p=0.022). No significant differences in gender, 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. Insulin levels and blood pressure was unaffected by treatment. No significant difference for ADAS‐Cog 13, CDR‐SOB or FAQ scores were found between treatment groups at 3 and 6 months. There was no impact of IN glulisine on depression or suicidality. Conclusion IN glulisine was safe and well‐tolerated and did not consistently impact peripheral glucose or insulin levels. There were no enhancing effects of IN glulisine on cognition, function, or mood, but the ability to detect significance was limited by number of subjects successfully enrolled and study duration. Additional investigations following a larger MCI/AD cohort inclusive of NIDDM subjects over a longer duration are necessary to better evaluate RA insulin efficacy in this population.