First-Ever Brain Imaging Of Nasal Insulin Brings Scientists Closer To New Alzheimer’s Therapy

Unprecedented Study Explains Why Alzheimer’s Nasal Spray Trials Keep Getting Mixed Results

WINSTON-SALEM, N.C. — For the first time, researchers have captured real-time images of insulin journeying from the nose directly into the human brain. Using advanced brain imaging, they discovered that people with early signs of memory problems process this hormone differently than those with healthy brains, a finding that may help guide future Alzheimer’s treatment strategies.

Nasal insulin therapy has emerged as a potential approach for Alzheimer’s because it bypasses the bloodstream and travels directly to the brain along nerve pathways. Unlike insulin injections used by diabetics, the nasal version doesn’t significantly affect blood sugar levels but may help restore normal brain signaling in people experiencing cognitive decline.

The research addresses a critical gap in understanding how potential therapies reach the brain. “Intranasal insulin (INI) is being explored to treat Alzheimer’s disease and other conditions. The method of intranasal delivery has been shown to affect outcomes, requiring validation prior to clinical investigation,” the researchers wrote in their paper, published in Alzheimer s & Dementia Translational Research & Clinical Interventions.

Current Alzheimer’s treatments offer limited benefits, and many adults cannot use newly approved anti-amyloid drugs due to other health conditions. This has driven scientists to explore alternative methods that may target underlying disease processes more directly than simply removing amyloid plaques from the brain.

How Scientists Track Nasal Insulin in Human Brain

Wake Forest University researchers recruited 16 older adults, averaging 72 years old, for the study. Seven had normal brain function, while nine showed mild cognitive impairment, which is often a precursor to Alzheimer’s disease. Participants ranged in age from about 61 to 85 years old, with 10 men and 6 women enrolled.

The study required extensive safety precautions. Participants fasted for several hours before their scans, and anyone with type 2 diabetes or taking anti-diabetic medications was excluded. Medical staff monitored vital signs including blood pressure, heart rate, and oxygen levels before, during, and after the procedure.

Each participant received six sprays of specially-labeled insulin through their nose using the Aptar Cartridge Pump System, a precision delivery device designed to target nasal areas where absorption into the brain is most effective. The device delivered a total of about 4 insulin units, significantly lower than typical diabetic doses but sufficient for brain imaging.

Scientists then used positron emission tomography (PET) scanning to track the insulin as it entered 11 key brain regions over 40 minutes, including areas critical for memory, emotional regulation, and consciousness. A follow-up whole-body scan tracked where else the insulin traveled.

The radioactive marker, called [68Ga]Ga-NOTA-insulin, allowed researchers to visualize insulin distribution and retention over time. Safety remained paramount: radiation exposure stayed well below international limits, and participants received follow-up calls within 48 hours to check for delayed reactions.

Memory-Impaired Brains Process Insulin Differently Than Healthy Brains

The brain scans revealed a notable pattern that could help explain inconsistent results in earlier clinical trials. People with normal cognition absorbed more insulin in five key regions: the hippocampus (memory), olfactory cortex (smell), amygdala (emotion), thalamus, and parahippocampus (memory support).

Timing also differed. Healthy brains reached peak insulin absorption around 12–13 minutes after the nasal spray and maintained elevated levels throughout the 40-minute scan. Brains with mild impairment peaked just 2–3 minutes in and cleared the insulin more quickly, suggesting impaired retention.

These differences were statistically significant. An analysis of area under the curve (AUC) — a measure of total insulin exposure over time — showed that people with cognitive impairment had lower insulin uptake in all brain regions compared to those with healthy cognition.

Gender differences emerged as well. Women showed particularly strong associations between vascular health and insulin uptake. Higher pulse pressure, a measure of arterial elasticity, correlated with better insulin absorption across multiple brain regions. This link wasn’t observed in men.

Women with higher levels of phosphorylated tau217, a blood marker linked to Alzheimer’s, also had lower insulin uptake across nearly all brain regions, suggesting that tau burden may interfere with brain insulin delivery or retention.

What This Means for Future Alzheimer’s Treatment

These discoveries may help explain why some nasal insulin trials for Alzheimer’s produced inconsistent results. If cognitively impaired brains absorb and process insulin differently than healthy ones, treatment strategies may need to be personalized rather than simply adjusting dosage.

The research affirms several key points. First, insulin can be successfully delivered to human brain regions affected by Alzheimer’s disease using specialized nasal devices. Second, early cognitive impairment alters how the brain processes this potential therapy, creating challenges that need tailored solutions.

Several biological mechanisms could underlie these differences. Amyloid plaques may obstruct the perivascular channels that normally transport insulin from the nasal cavity into the brain. Reduced arterial pulsations—common with aging—may further limit delivery. Damaged insulin receptors could also reduce uptake once insulin reaches its destination.

Safety concerns that once hindered insulin-based therapies proved unfounded in this trial. “An important finding from this study was that intranasal administration of [68Ga]Ga-NOTA-insulin is safe for older adults,” the researchers emphasized. Blood sugar levels remained stable, and no serious side effects occurred.

The study also validated the delivery system used, the Aptar Cartridge Pump System, which reliably transported insulin to multiple brain areas. This is especially important because previous studies found that different nasal devices vary in effectiveness.

Moving forward, larger studies are needed to confirm these results across more diverse populations and to explore how genetic factors, like APOE genotype, influence insulin uptake and clinical outcomes. Researchers also hope to examine whether the observed uptake differences lead to differing therapeutic responses when insulin is used to treat Alzheimer’s rather than simply visualized.

The team concluded: “Our results show that intranasal administration of [68Ga]Ga-NOTA-insulin is safe and delivers insulin to multiple brain regions that support cognition and are affected by AD pathology.” This study offers the first direct visualization of nasal insulin reaching those brain regions, while revealing that cognitive impairment presents unique challenges for one of medicine’s most difficult diseases.

Disclaimer: This study involved brain imaging, not treatment testing. While the findings demonstrate that nasal insulin reaches key brain regions, the research did not assess clinical outcomes such as memory improvement or disease progression. Future trials are needed to determine whether these delivery patterns affect therapeutic response in Alzheimer’s disease.