A new study has provided the most direct evidence yet that intranasal insulin—a proposed metabolic therapy for Alzheimer’s disease—reaches critical brain regions involved in memory and cognition. Published in Alzheimer’s & Dementia: Translational Research & Clinical Interventions, the research from Wake Forest University School of Medicine validates intranasal insulin delivery using cutting-edge positron emission tomography (PET) imaging, a crucial step toward advancing future clinical trials.

Intranasal insulin has long been considered a promising alternative to traditional Alzheimer’s treatments, particularly in light of the mixed efficacy and side effects of anti-amyloid drugs. Insulin resistance is a known risk factor for Alzheimer’s, and small pilot studies have hinted that insulin delivered directly to the brain may improve memory in people with mild cognitive impairment (MCI). But a major challenge has remained: no prior study had definitively proven that intranasal insulin reaches the brain regions where it is needed.

“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 and senior author of the paper. “We needed direct evidence that the drug is able to reach key brain targets.”

First PET confirmation of brain uptake

The team recruited 16 older adults (average age 72), including seven cognitively normal participants and nine with MCI. Using a specialized six-spray nasal device and a novel radiotracer, [68Ga]Ga-NOTA-insulin, they performed 40-minute PET brain scans followed by whole-body imaging.

The results were striking. Elevated insulin uptake was observed in 11 brain regions crucial for memory and cognition, including the hippocampus, olfactory cortex, amygdala, and temporal lobe. Only two participants reported mild headaches, which resolved within 24 hours, confirming the procedure’s safety.

Crucially, the study revealed different brain uptake patterns depending on cognitive status. Cognitively normal participants exhibited higher overall uptake and a slower clearance rate, whereas those with MCI showed rapid initial uptake followed by faster clearance, suggesting altered insulin transport or metabolism in early cognitive decline.

The authors note in the paper, “Uptake patterns in individuals with MCI suggest altered pharmacokinetics that may influence treatment responsiveness.”

Implications for personalized Alzheimer’s therapies

The findings may explain why past clinical trials of intranasal insulin in Alzheimer’s have produced mixed results. If people with MCI absorb and clear insulin differently, dosing strategies may need to be adjusted.

Craft emphasizes that this study provides a “roadmap” for future therapeutic trials. “An unexpected finding was the observation that uptake may differ in people with early cognitive decline. This means we’re no longer flying blind; we now have a roadmap directly to the brain,” she said.

The study also highlighted sex and biomarker differences. In women, insulin uptake correlated strongly with cardiovascular health markers, and elevated ptau217 levels—a marker of Alzheimer’s pathology—were linked to decreased insulin absorption across multiple brain regions. This finding could guide future stratification of patients in clinical trials.

Context: Beyond amyloid-targeting drugs

The timing of this work is significant. Current FDA-approved Alzheimer’s drugs, such as anti-amyloid antibodies, have shown limited clinical benefit and carry risks of brain swelling and bleeding. By contrast, intranasal insulin is inexpensive, non-invasive, and has decades of safety data in diabetes research.

Moreover, the PET validation strategy could apply to other intranasal therapies aimed at neurological diseases, including Parkinson’s and frontotemporal dementia. As Craft notes in the paper, “Validating target engagement is an essential prerequisite to designing successful therapeutic trials.”

The study also underscores a broader shift toward metabolic and precision medicine approaches in Alzheimer’s research. Understanding how individual factors—such as vascular health, amyloid burden, or sex—affect drug delivery to the brain could help identify which patients are most likely to benefit.

What’s next?

The Wake Forest team plans larger studies within the next 12–18 months to explore how vascular health and amyloid accumulation influence brain insulin delivery. If confirmed, these findings could pave the way for personalized intranasal insulin therapies aimed at slowing or preventing Alzheimer’s progression.

As Craft summed up: “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.”