Scientists have found that a widely prescribed diabetes medication, when paired with nasal insulin, safely improved brain health in people with early Alzheimer’s disease, marking a potential shift in how doctors might approach the condition beyond recently approved drugs that target amyloid plaques.
The four-week trial from Wake Forest University School of Medicine tested empagliflozin, sold as Jardiance, in 47 older adults with mild cognitive impairment or early Alzheimer’s. None of the participants had diabetes. Researchers wanted to see if targeting the brain’s metabolic problems, rather than just clearing protein buildup, could help preserve memory and thinking skills.
Both medications were safe and well-tolerated, with side effects no worse than placebo. The nasal insulin device earned high marks from users, who rated it 4.6 out of 5 for ease of use, and participants stuck with the treatment protocol more than 97% of the time.
“Our study suggests that targeting metabolism can change the course of Alzheimer’s disease. For the first time, we found that empagliflozin, an established diabetes and heart medication, reduced markers of brain injury while restoring blood flow in critical brain regions.”
The results revealed different benefits for each medication. Intranasal insulin improved performance on sensitive cognitive tests designed to catch early memory changes. Brain scans showed the treatment strengthened white matter connections and altered blood flow patterns in memory-critical regions. It also reduced a marker of dysfunction in astrocytes, the support cells that maintain healthy connections between blood vessels and brain cells.
Two Drugs, Different Targets
Empagliflozin worked through separate mechanisms. The medication significantly lowered cerebrospinal fluid tau, a protein that forms toxic tangles in Alzheimer’s brains. It also reduced neurogranin, a marker linked to disease progression, and changed blood flow in key brain regions. Perhaps most interesting: empagliflozin increased HDL cholesterol, showing its metabolic effects work even in people without diabetes.
Both medications influenced multiple immune and inflammatory proteins throughout the brain and bloodstream. The changes suggest the drugs help activate protective immune responses while tamping down harmful inflammation. Intranasal insulin particularly affected proteins involved in the nasal-olfactory plexus, a recently discovered pathway connecting the brain’s waste-clearance system to immune systems throughout the body.
The medications tackle overlapping problems from different angles. Empagliflozin, originally developed for diabetes, improves how the body processes glucose and sodium, leading to better insulin sensitivity and vascular health. The drug also reduces oxidative stress and inflammation while improving how mitochondria produce energy in cells.
Targeting Upstream Problems
Intranasal insulin uses a precision delivery device to send insulin directly into the brain through the nose, bypassing the bloodstream. Once there, insulin activates receptors that keep synapses healthy, support blood vessel function, maintain white matter integrity, and regulate immune responses. The trial used higher insulin doses than previous studies, 160 units daily versus 40 to 80 units, delivered through a cartridge pump system that provides precise, reliable delivery to brain regions involved in memory and cognition.
People with Alzheimer’s often have insulin resistance in the brain alongside vascular problems that reduce blood flow and nutrient delivery. These metabolic disruptions speed up the accumulation of amyloid plaques and tau tangles while preventing the brain from clearing these toxic proteins. Both medications tested in this trial target these upstream problems.
“We plan to build on these promising results with larger, longer studies in people with early and preclinical Alzheimer’s disease. Because empagliflozin or intranasal insulin improved tau tangles, cognition, neurovascular health and immune function, we believe these treatments could offer real therapeutic potential, either on their own or in combination with other Alzheimer’s therapies.”
The complementary effects of the two medications could make them valuable additions to combination therapy approaches. Since both drugs are already FDA-approved for other conditions with well-established safety profiles, they could reach patients faster than entirely new medications would. That matters for families facing a disease where recently approved anti-amyloid drugs offer modest benefits but come with side effects and medical contraindications that make them unavailable to many patients.
The study enrolled participants with an average age of 70. Treatment-related side effects were mild and similar across all groups. The most common were nasal irritation and vaginal yeast infections, with no differences in rates between treatment groups and placebo.
This marks the first time empagliflozin has been tested in non-diabetic patients with Alzheimer’s disease. The Alzheimer’s Association funded the study through its Part the Cloud program, which has raised nearly 90 million dollars to fund 72 clinical trials targeting different aspects of the disease. The program operates on the growing consensus that effective treatment will likely require personalized combinations of multiple interventions.
Alzheimer’s & Dementia: 10.1002/alz.70704
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