The study was meticulously structured to evaluate not only clinical outcomes but also to assess the practicality of administering low-dose lithium within this sensitive population. Mild cognitive impairment represents a transitional state between normal cognitive aging and more severe forms of dementia, including Alzheimer’s disease, making early intervention strategies critically important. Lithium, known for its mood-stabilizing properties in psychiatric disorders, has garnered attention because of its neuroprotective mechanisms demonstrated in preclinical models, including the modulation of glycogen synthase kinase-3 beta (GSK-3β) and enhancement of neurotrophic factors.

In this pilot trial, recruitment protocols, randomization procedures, and lithium dosing regimens were carefully optimized to ensure participant safety and treatment adherence. The investigators employed rigorous monitoring to detect any adverse effects, given lithium’s known narrow therapeutic window and renal considerations. Results confirmed that the low-dose lithium was generally well tolerated, and no severe safety issues or intolerability emerged, establishing a favorable profile for further research exploration.

Despite these positive indicators regarding feasibility and safety, the trial did not achieve the prespecified significance in its coprimary outcomes, which were designed to measure changes in neuropsychological performance and biomarkers indicative of cognitive decline. This lack of statistical significance may be attributed to the pilot nature of the trial, including its limited sample size and relatively brief intervention period, which constrained its power to detect subtle cognitive benefits.

The importance of effect size estimation, nevertheless, cannot be understated; the trial generated crucial data that will inform power analyses and sample size calculations in future randomized controlled trials. Effect size estimates help researchers understand the magnitude of lithium’s impact on cognitive indices, consequently shaping hypothesis refinement and methodological adjustments necessary for definitive testing.

Furthermore, this study contributes to the growing body of clinical neuroscience literature that seeks to translate promising molecular and cellular findings into tangible therapeutic advances. The neurobiology of lithium’s action encompasses modulation of signaling cascades implicated in neurodegeneration, anti-inflammatory effects, and the facilitation of synaptic plasticity. These multifaceted mechanisms underpin the rationale for lithium’s repositioning as a candidate treatment for cognitive impairment.

The trial underscores both challenges and opportunities inherent in clinical trials involving neuropsychiatric medications repurposed for cognitive disorders. The intricacies of conducting randomized, double-blind, placebo-controlled studies in older adults with MCI demand attention to ethical considerations, comorbidities, polypharmacy, and the heterogeneity of cognitive trajectories.

In addition to quantifiable measures, patient-reported outcomes and functional assessments were integrated to provide a comprehensive understanding of lithium’s impact on daily living and quality of life parameters. Although definitive clinical efficacy was not demonstrated, the safety profile observed encourages ongoing investigation.

Importantly, this pilot trial creates a template for future studies to incorporate biomarkers such as cerebrospinal fluid tau and beta-amyloid levels, neuroimaging metrics like hippocampal volume, and advanced cognitive testing batteries. Adopting such multidimensional endpoints will enhance the sensitivity and specificity of detecting potential therapeutic signals.

The lead investigator, Dr. Ariel G. Gildengers, and the research team emphasize the preliminary nature of these findings and advocate for larger, longer-duration trials to conclusively evaluate the neuroprotective potential of low-dose lithium. Such trials could elucidate whether lithium truly alters disease progression or primarily offers symptomatic benefit.

This incremental research approach exemplifies how pilot studies serve an indispensable role in clinical translation, informing not just the scientific understanding but also the operational and logistical facets of complex interventions in at-risk populations. As the global burden of cognitive disorders escalates, optimization of such early-phase studies will be vital for delivering safe, effective treatment modalities.

The present research is published in the renowned journal JAMA Neurology, reflecting its significance in the clinical neuroscience community. While this initial pilot does not provide definitive answers regarding low-dose lithium’s efficacy, it firmly positions lithium as a candidate worthy of continued scientific scrutiny within the quest to delay or prevent cognitive decline associated with neurodegenerative conditions.

Subject of Research: Low-dose lithium treatment in mild cognitive impairment
Article Title: Not provided
News Publication Date: Not provided
Web References: Not provided
References: doi:10.1001/jamaneurol.2026.0072
Image Credits: Not provided

Keywords: Cognition, Cognitive disorders, Medical treatments, Clinical trials, Randomization, Medications, Drug therapy, Neurology

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