Growing Evidence Suggests GLP-1s May Play a Role in Alzheimer’s Disease

Recent research has unveiled exciting findings indicating that Novo Nordisk’s GLP-1 medications, semaglutide (available as Ozempic and Wegovy) and liraglutide, may offer protective benefits against Alzheimer’s disease or cognitive decline. These findings provide a new perspective on how this popular class of therapeutics could contribute to combating the debilitating disorder characterized by memory loss.

A recent article in Alzheimer’s and Dementia highlighted a real-world study, which revealed that individuals diagnosed with type 2 diabetes and treated with semaglutide experienced a significant reduction—between 40% and 70%—in their risk of receiving an Alzheimer’s diagnosis. This discovery follows the previous findings from a Phase II trial assessing liraglutide, Novo’s earlier GLP-1 (marketed as Saxenda for weight management and Victoza for type 2 diabetes), which showed a slower cognitive function decline among treated patients compared to those receiving a placebo. Results from that trial were shared at the Alzheimer’s Association International Conference in July.

Christian Hölscher, co-founder and chief scientific officer at Kariya Pharmaceuticals, which focuses on neurodegeneration, expressed optimism, stating, “I think we are at the verge of a revolution.”

Conversely, George Perry, a neuroscientist from the University of Texas at San Antonio, advised caution, suggesting that GLP-1s might serve a preventive role in Alzheimer’s, although he did not exclude the potential for them to modify the disease. He noted, “there’s evidence . . . that there’s really a profound metabolic change in the person during Alzheimer’s disease.”

Despite various preclinical studies demonstrating the benefits of GLP-1 receptor agonists in addressing the fundamental aspects of Alzheimer’s, there remains a lack of data from clinical trials, as highlighted in a recent Journal of Alzheimer’s Disease Reports publication. However, expectations are high as Novo anticipates the results from two large Phase III studies, EVOKE and EVOKE Plus, which are evaluating semaglutide’s effects on Alzheimer’s patients. Both trials are projected to finish by September 2025.

“I’m confident that we will see some effects in the Novo Nordisk trials . . . because everything we’ve seen so far supports this concept,” Hölscher remarked to BioSpace. “We know this is a worthwhile target and it definitely should be pursued.”

The Diabetes-Alzheimer’s Connection

Utilizing GLP-1 medications for Alzheimer’s isn’t a novel concept, as pointed out by Graig Suvannevejh, senior biopharmaceutical and biotechnology equity research analyst at Mizuho Americas. He noted the longstanding curiosity surrounding drugs aimed at metabolic and endocrine diseases impacting Alzheimer’s. Perry acknowledged a link he described as the “intersection of diabetes and midlife obesity with Alzheimer’s disease.”

Research has established correlations between insulin resistance and Alzheimer’s, sparking interest in labeling Alzheimer’s as “type 3 diabetes.” Numerous observational studies and meta-analyses have linked type 2 diabetes to a heightened risk of developing Alzheimer’s.

Howard Fillit, co-founder and chief science officer at the Alzheimer’s Drug Discovery Foundation (ADDF), emphasized that increasing insulin resistance with aging affects glucose uptake, potentially leading to chronic neuronal dysfunction and death. This insight supports the idea that GLP-1s, by enhancing insulin secretion and regulating glucagon, could help mitigate the risk of Alzheimer’s disease.

Growing Body of Evidence

As the medical community awaits the outcomes of Novo’s EVOKE studies, the potential for GLP-1s in both preventing and managing Alzheimer’s is becoming increasingly evident. Perry, who contributed to the previous study involving semaglutide, urged caution when interpreting results but highlighted their importance in revealing the metabolic framework of Alzheimer’s.

The outcomes of the Phase II liraglutide trial echoed similar findings. With 204 participants distributed across multiple UK sites, those on liraglutide experienced an 18% slower decline in cognitive function compared to the placebo group over a year. Paul Edison, an Imperial College London professor of science and the study’s leader, noted that the slower decrease in brain volume suggests liraglutide’s protective qualities for the brain, akin to the protective functions of statins for the heart.

Kariya Pharmaceuticals is also pursuing KP405, a pioneering dual GLP-1/GIP receptor agonist initially aimed at Parkinson’s, with intentions to explore its applicability for Alzheimer’s. Hölscher previously stated that while liraglutide and semaglutide are effective for diabetes management, their design may limit brain access. Modifying KP405 to enhance brain delivery without the usual side effects seen in standard GLP-1s is a key goal.

Despite the absence of clinical trials involving Eli Lilly’s tirzepatide in the context of Alzheimer’s, Suvannevejh acknowledged a logical alignment between the compound and Alzheimer’s-focused research given Lilly’s neurological emphasis. Lilly has recently introduced Kisunla, which was approved as the third disease-modifying treatment for the disorder in July.

Still To Prove

However, even with these promising indicators, a consensus among experts indicates that GLP-1s must substantiate their value for Alzheimer’s thoroughly. Perry highlighted the necessity for comprehensive investigations demonstrating their efficacy in significantly reducing the disease’s incidence. This entails large-scale random controlled trials, which pose their own challenges, particularly for populations at lower risk of progression.

Safety remains a pertinent issue as well; establishing the long-term safety of GLP-1s will be vital if patients are to use these drugs frequently for Alzheimer’s. “You have to worry about side effects,” Perry said, emphasizing the importance of monitoring the drugs for chronic use.

Hölscher also raised concerns about the safety and efficacy of anti-amyloid antibodies such as Kisunla and Biogen/Eisai’s Leqembi, expressing doubt about their practicality given their minimal impacts on patients. Notably, he boldly asserted regarding Novo’s upcoming studies: “If those trials show even a small effect, the amyloid strategy will be dead in the water.”