A clinical trial from Wake Forest University School of Medicine shows that two widely available medications, thediabetesdrugempagliflozin(Jardiance) and intranasalinsulin, safely improve brain health in people with mild cognitive impairment and early Alzheimer’s disease. The study, published inAlzheimer’s & Dementia, the journal of the Alzheimer’s Association, marks the first time empagliflozin has been tested in non-diabetic patients withAlzheimer’s disease. The results show promising effects on memory,brain healthand brain blood flow. The research addresses a critical treatment gap for patients with Alzheimer’s disease. While recently approved anti-amyloid drugs represent progress, their benefits are modest, and they’re unavailable to many patients due to side effects and medical contraindications. They also don’t address the upstream metabolic and vascular problems that drive disease progression or help restore brain function after damage occurs. “Our study suggests that targeting metabolism can change the course of Alzheimer’s disease,” said Suzanne Craft, Ph.D., lead investigator and professor of medicine and director of the Wake Forest Alzheimer’s Disease Research Center. “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. We also confirmed that delivering insulin directly to the brain with a newly validated device enhances cognition, neurovascular health and immune function. Together, these findings highlight metabolism as a powerful new frontier in Alzheimer’s treatment.” The four-week trial enrolled 47 older adults (average age 70) with mild cognitive impairment or early Alzheimer’s disease. Participants were randomly assigned to receive intranasal insulin alone, empagliflozin alone, both medications together or a placebo. Both medications were safe and well-tolerated. Treatment-related side effects were mild and similar across all groups. Participants found the nasal insulin device highly feasible to use (4.6 out of 5.0), and compliance rates exceeded 97% for both medications throughout the study. The results revealed different benefits for each medication. Intranasal insulin improved performance on sensitive cognitive tests that detect early memory and thinking changes. Brain imaging showed insulin treatment increased the structural integrity of white matter connections and changed blood flow patterns in memory-critical regions. The treatment also reduced plasma GFAP, a marker of astrocyte (support cells that maintain healthy connections between blood vessels and brain cells) dysfunction that’s elevated in Alzheimer’s disease. Empagliflozin had different effects. The medication significantly lowered cerebrospinal fluid tau, a protein that forms toxic tangles in the brain in patients with Alzheimer’s disease. It also reduced neurogranin and vascular markers linked to disease progression and changed blood flow in key brain regions. Empagliflozin also increased HDL cholesterol, showing its beneficial metabolic effects work even in non-diabetic patients. Both medications influenced multiple immune and inflammatory proteins in cerebrospinal fluid and blood. The changes suggest the drugs help activate protective immune responses while reducing harmful inflammation. Intranasal insulin particularly affected proteins involved in the nasal-olfactory plexus, a newly discovered pathway that connects the brain’s waste-clearance system to immune systems throughout the body. The medications work differently but target overlapping problems. Empagliflozin, originally developed for diabetes, improves how the body processes glucose and sodium. That leads to better insulin sensitivity and vascular health throughout the body and brain. The drug also reduces oxidative stress and inflammation while improving how mitochondria produce energy in cells. 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 throughout the brain that keep synapses healthy, support blood vessel function, maintain white matter integrity, and regulate immune responses. Previous studies showed that lower doses of intranasal insulin preserved brain glucose metabolism and slowed white matter damage over 12 months. The trial used higher insulin doses than previous studies (160 IU daily versus 40-80 IU) delivered through a cartridge pump system developed by Aptar Pharma and validated in earlier brain imaging studies. This device provides precise, reliable delivery to brain regions involved in memory and cognition. Empagliflozin was given at the standard 10 mg daily dose used for cardiovascular conditions in non-diabetic adults. People with Alzheimer’s disease often have insulin resistance in the brain alongside vascular problems that reduce blood flow and nutrient delivery. These metabolic and vascular 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,” Craft said. “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. The study was supported by the Alzheimer’s Association through its “Part the Cloud” program. Started by philanthropist Michaela “Mikey” Hoag and the Alzheimer’s Association, “Part the Cloud” provides strategic funding to advance promising investigational Alzheimer’s therapies into clinical trials. The treatment targets are varied, which is important given the growing consensus that effective treatment and prevention of Alzheimer’s is likely to be a personalized combination of multiple interventions targeting different aspects of the disease. “Part the Cloud” has raised nearly $90 million to fund 72 clinical trials with the highest probability of slowing, stopping or ultimately curing Alzheimer’s disease. Jennifer M. Erichsen, Thomas C. Register, Courtney Sutphen, Da Ma, Sarah A. Gaussoin, Marc Rudolph, Melissa Rundle, James T. Bateman, Samuel N. Lockhart, Kiran K. Solingapuram Sai, Christopher Whitlow, Suzanne Craft, A phase 2A/B randomized trial of metabolic modulators intranasal insulin and empagliflozin for MCI and early AD, Alzheimer’s & Dementia, https://doi.org/10.1002/alz.70704