In a groundbreaking clinical trial that challenges traditional understandings of Alzheimer’s disease treatment, researchers from Wake Forest University School of Medicine have unveiled promising results with two metabolic drugs: empagliflozin and intranasal insulin. This landmark study, published recently in Alzheimer’s & Dementia, explores the effects of these medications on individuals diagnosed with mild cognitive impairment (MCI) and early-stage Alzheimer’s disease (AD), suggesting an innovative and potentially transformative approach to combat this pervasive neurodegenerative illness.
The trial is notable for being the first to administer empagliflozin—a drug primarily used for diabetes and cardiovascular health—to non-diabetic patients with Alzheimer’s. Empagliflozin belongs to the class of sodium-glucose cotransporter 2 (SGLT2) inhibitors, which helps regulate glucose reabsorption in the kidneys, thereby improving systemic insulin sensitivity and cardiovascular outcomes. The decision to investigate it in a neurological context stems from growing evidence that metabolic dysfunction and vascular impairment are critical drivers in the pathogenesis of Alzheimer’s, beyond the classical amyloid-beta and tau protein perspectives.
Alzheimer’s disease has long been characterized by accumulations of amyloid plaques and tau tangles in the brain, but recent emphasis on metabolic and vascular contributors provides a fresh frontier for therapeutic strategies. Traditional anti-amyloid medications, while a significant step forward, offer only modest benefits and are restricted in use due to side effects and contraindications. These drugs also fail to address upstream dysfunctions in brain metabolism and blood flow, which fuel neurodegeneration and cognitive decline. Thus, the Wake Forest study positions metabolism as a strategic target to slow or potentially halt disease progression.
Led by Suzanne Craft, Ph.D., director of the Wake Forest Alzheimer’s Disease Research Center, the study enrolled a cohort of 47 older adults averaging 70 years of age. Participants with mild cognitive impairment or early Alzheimer’s were randomized into four groups: intranasal insulin alone, empagliflozin alone, both drugs combined, or placebo. The trial’s design meticulously aimed at dissecting the differential and potentially synergistic impacts of these metabolic modulators on brain function and pathology.
Intranasal insulin was administered through a novel, precision-engineered cartridge pump device developed by Aptar Pharma, designed to deliver the peptide hormone directly into the central nervous system via the nasal-olfactory route. This delivery circumvents the systemic circulation and blood-brain barrier, enabling targeted activation of insulin receptors across synapses, vasculature, and glial support cells. Insulin signaling in the brain plays a pivotal role in maintaining synaptic plasticity, cerebral blood flow, white matter integrity, and immune regulation—all processes impaired in Alzheimer’s pathology.
Over the course of four weeks, the intranasal insulin group exhibited significant cognitive enhancements, particularly in sensitive tasks assessing memory and executive functions, areas commonly compromised in early Alzheimer’s. Neuroimaging confirmed increased white matter structural integrity and modulated regional cerebral blood flow patterns in areas critical to memory. Moreover, the treatment lowered levels of plasma glial fibrillary acidic protein (GFAP), an astrocyte dysfunction biomarker implicated in neuroinflammatory responses and blood-brain barrier disruption.
In contrast, empagliflozin showed a distinct yet complementary biochemical effect. Cerebrospinal fluid analyses revealed a marked reduction in tau protein concentrations, a hallmark of AD neurofibrillary degeneration. Additionally, decreases in neurogranin—a postsynaptic protein involved in synaptic plasticity—and vascular injury markers suggest empagliflozin acts to mitigate synaptic loss and microvascular dysfunction, key drivers in cognitive decline. The drug’s capacity to elevate high-density lipoprotein (HDL) cholesterol further confirms its broad metabolic benefits, extending beyond glycemic control into neurovascular health.
Interestingly, both medications exerted immunomodulatory effects, influencing cerebrospinal fluid and systemic inflammatory mediator levels. The data indicate activation of protective immune pathways while dampening deleterious neuroinflammation, a central component of Alzheimer’s pathophysiology. The unique impact of intranasal insulin on proteins associated with the nasal-olfactory plexus highlights its potential to leverage the brain’s glymphatic and immune clearance systems, which are increasingly recognized for their roles in waste removal and neuroimmune communication.
This bifurcated mechanism—empagliflozin’s systemic metabolic and vascular enhancement paired with intranasal insulin’s direct neurotrophic and immune-modulating actions—offers a complementary therapeutic paradigm. Empagliflozin’s ability to reduce oxidative stress and support mitochondrial energetics further bolsters cellular resilience against degenerative insults, while intranasal insulin promotes synaptic maintenance and vascular regulation critical for cognitive preservation.
The clinical trial affirmed the safety and tolerability of both agents in non-diabetic participants, with high adherence rates and minimal mild side effects uniformly across study arms. The intranasal device received excellent user acceptability scores, crucial for potential long-term treatment feasibility. Despite the relatively short duration of four weeks, these mechanistic and functional changes provide compelling evidence for extending and scaling such interventions.
Looking forward, the research team plans to pursue larger, longer-duration studies, including subjects in preclinical stages of Alzheimer’s, to validate and expand upon these encouraging findings. The prospect of combining metabolic modulators like empagliflozin and intranasal insulin with existing and emerging Alzheimer’s therapies may revolutionize the treatment landscape, offering personalized, multifaceted strategies that target the diverse pathological processes driving this disease.
Because both empagliflozin and intranasal insulin are FDA-approved for other indications with established safety profiles, their repurposing for Alzheimer’s could expedite clinical availability, an urgent need in a field where therapeutic options remain limited. This study exemplifies a promising shift towards addressing the metabolic and vascular roots of neurodegeneration rather than solely focusing on amyloid and tau pathology.
The research was generously funded by the Alzheimer’s Association’s “Part the Cloud” initiative, which supports innovative clinical trials aimed at slowing, stopping, or curing Alzheimer’s disease. This philanthropic effort, sparked by Michaela “Mikey” Hoag and others, has mobilized nearly $90 million to propel diverse investigational treatments through clinical pipelines, reflecting the complex and multifactorial nature of Alzheimer’s requiring tailored combination therapies.
In summary, the Wake Forest trial offers compelling evidence that targeting brain metabolism and vascular health using empagliflozin and intranasal insulin can modulate pathological markers, improve cognition, and normalize neurovascular and immune functions in early Alzheimer’s disease. These promising metabolic modulators could help close the significant therapeutic gaps unaddressed by existing Alzheimer’s treatments, heralding a new era of precision medicine in neurodegenerative disease management.
Subject of Research: People
Article Title: A phase 2A/B randomized trial of metabolic modulators intranasal insulin and empagliflozin for MCI and early AD
News Publication Date: October 16, 2025
Web References:
Alzheimer’s & Dementia Journal Article
Wake Forest University School of Medicine
Keywords: Alzheimer disease, neurodegenerative diseases, dementia, diabetes, insulin
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