Intranasal insulin can safely and effectively reach key brain regions involved in memory and cognition in older adults, according to a first-in-human imaging study published in Alzheimer's & Dementia: Translational Research & Clinical Interventions. The findings mark an essential step toward validating this drug delivery method to treat Alzheimer's disease and mild cognitive impairment (MCI).
"This study fills a critical gap in our understanding of how intranasal insulin reaches the brain," said Suzanne Craft, PhD, professor of gerontology and geriatric medicine at Wake Forest University School of Medicine and director of the Wake Forest Alzheimer's Disease Research Center. "We needed direct evidence that the drug is able to reach key brain targets."
Study Design and Methodology
The study enrolled 16 older adults with a mean age of 72 years, including 7 cognitively normal individuals and 9 with MCI. Using the radiolabeled insulin compound [68Ga]Ga-NOTA-insulin delivered with an Aptar Cartridge Pump System, participants underwent 40-minute PET brain scans to measure insulin uptake in real time.
The delivery system was specifically designed to optimize deposition in the upper nasal cavity, near the olfactory and trigeminal nerves. The insulin then binds to receptors in the cortex and hippocampus to overcome central nervous system insulin resistance and elicit downstream effects.
Key Brain Regions Successfully Targeted
The insulin reached 11 memory- and cognition-related brain regions with significant uptake observed across all participants. These critical areas included the hippocampus, amygdala, thalamus, temporal lobe, and olfactory cortex. The scans revealed elevated insulin uptake in these areas that are essential for memory formation and cognitive function.
Differential Uptake Patterns Observed
One unexpected finding was that insulin uptake varied among patients with early cognitive decline. Average insulin uptake was higher in cognitively normal adults than in those with MCI, who demonstrated faster clearance and lower cumulative insulin delivery.
Researchers identified several possible reasons for this discrepancy. One is disruption of the recently described nasal-olfactory plexus, a pathway facilitating cerebrospinal fluid exchange and nose-to-brain drug delivery. This pathway can be impaired by factors like amyloid buildup, which is common in MCI and Alzheimer's disease.
A second factor is vascular function. Among cognitively normal participants, higher pulse pressure—a sign of better arterial elasticity—was associated with increased insulin delivery, but this relationship was absent in the MCI group. Finally, MCI may involve reduced insulin receptor expression in the brain, limiting the capacity for insulin binding and prolonging therapeutic effect.
Safety Profile and Biomarker Correlations
No serious adverse events were reported in the study, and only 2 participants experienced mild, self-resolving headaches. Systemic insulin and glucose levels remained stable with intranasal insulin, as did systolic and diastolic blood pressure. Although plasma glucose levels decreased over time with the spray, levels remained well above hypoglycemic cutoffs of 70 mg/dL.
In addition to cognitive status, insulin uptake varied by sex, vascular health, and levels of plasma p-tau217—a biomarker associated with amyloid pathology in Alzheimer's disease. Among female participants, higher pulse pressure and baseline insulin were associated with greater brain insulin absorption, while elevated p-tau217 levels were linked to less absorption in many regions of the brain.
Clinical Implications and Future Directions
The findings show promise in validating intranasal delivery systems effectively, which Craft said is an important step before starting therapeutic trials. "This means we're no longer flying blind," she said. "We now have a roadmap directly to the brain."
The Wake Forest team plans larger studies within the next one to two years to explore other factors that might influence brain insulin delivery, such as blood vessel health, amyloid beta plaques and sex differences.
"One of the biggest challenges in developing treatments for brain diseases is getting agents into the brain," Craft said. "This study shows we can validate intranasal delivery systems effectively, an essential step before launching therapeutic trials."
The findings also explain why some patients might respond better to intranasal insulin than others, providing crucial information for designing successful therapeutic trials. "There's an urgent need to identify effective and feasible ways to prevent and treat Alzheimer's dementia," Craft said. "These findings show that we can now validate whether treatments are actually reaching their intended brain targets, which is critical information for designing successful trials."
