GLP-1s have transformed obesity and diabetes management, but their potential may extend far beyond metabolic health. Emerging research suggests this drug class may hold promise for neurological and psychiatric conditions, including Alzheimer’s, Parkinson’s, and mood disorders such as anxiety and depression. As clinical trials push the boundaries of GLP-1’s therapeutic reach, we may be on the cusp of a paradigm shift in neurology.
GLP-1 and Alzheimer's Disease
For years, researchers have noted a link between diabetes and Alzheimer’s disease (AD). Insulin resistance, chronic inflammation, and metabolic dysfunction—hallmarks of diabetes—are also understood to contribute to neurodegeneration. Given this overlap in mechanisms, could GLP-1s help slow cognitive decline in AD?
Early data suggest that brain penetration plays a role in the cognitive effects of GLP-1s. Among commercially available options, dulaglutide exhibits the highest brain uptake (61.8%) (1). In contrast, exenatide and lixisenatide show significantly lower brain uptake, at 28% and 14% of dulaglutide’s levels respectively, while liraglutide, semaglutide, and tirzepatide demonstrate virtually no direct brain penetration. Notably, dulaglutide is the GLP-1 with the most robust clinical evidence supporting its cognitive effects, as demonstrated in a large placebo-controlled trial where it reduced cognitive impairment by 14% in diabetes patients (2).
Intriguingly, Novo Nordisk’s Phase IIb trial of liraglutide, which exhibits poor brain penetration, still reported a significant reduction in cognitive decline over one year, suggesting alternative mechanisms may be at play (3). Some evidence indicates that these compounds might reach the brain through indirect pathways, such as serum albumin binding or transport across the ventricular walls. This raises the possibility that GLP-1s could confer neuroprotective benefits even in the absence of significant brain penetration.
More definitive answers should come later this year when Novo Nordisk releases results from its Phase III EVOKE and EVOKE Plus trials, which are testing semaglutide in AD. Given the modest impact of current anti-amyloid therapies, positive results from these GLP-1 trials could dramatically alter AD treatment strategies.
Given the modest impact of current anti-amyloid therapies, positive results from these GLP-1 trials could dramatically alter AD treatment strategies.
GLP-1 and Parkinson’s Disease
While research into Alzheimer’s is more advanced, similar questions about the therapeutic potential of GLP-1s have also been raised in Parkinson’s disease. The connection between diabetes and PD remains unclear, but studies suggest that people with diabetes have up to a 40% higher risk of developing PD, and those with both conditions often experience faster motor symptom progression (4).
So far, clinical evidence for GLP-1s in Parkinson’s Disease has been disappointing. Recent and highly anticipated results from two exenatide trials failed to show meaningful benefits for PD, raising doubts about the viability of this therapeutic approach (5, 6).
So far, clinical evidence for GLP-1s in Parkinson’s Disease has been disappointing.
However, other studies show more promise, particularly in earlier stages of the disease. A Phase II trial of Sanofi’s lixisenatide demonstrated a slowing of motor disability progression in participants with early PD, though gastrointestinal side effects were a significant concern (7). Similarly, a study of NLY01—a brain-penetrant analog of exenatide—failed to show an overall benefit, but subgroup analysis suggested potential effects in younger patients (8).
Future research will need to focus on more targeted compounds and better patient stratification to conclude whether GLP-1s can modify PD progression or offer symptomatic relief.
GLP-1 and Psychiatric Disorders
GLP-1s are also gaining attention for their potential psychiatric benefits. A 2024 study analyzing electronic health records from 4 million patients linked semaglutide to lower rates of anxiety and depression diagnoses (9). This aligns with broader research suggesting a strong link between metabolic dysfunction and mental health disorders:
Type 2 diabetes is disproportionately common in people with mood disorders, including bipolar disorder, schizophrenia, and major depression (10).
Reversing insulin resistance has been shown to improve both mood and cognitive function in bipolar patients—suggesting that metabolic regulation itself may be therapeutic (11).
Some studies suggest GLP-1s may affect the mesolimbic reward system and hippocampus, key brain regions involved in both metabolic regulation and emotional processing (12).
Dozens of ongoing clinical trials are exploring whether GLP-1s could help treat these disorders (13). There’s also early evidence suggesting that GLP-1s may reduce cravings and relapse rates in addiction by modulating dopamine pathways (14). If these findings hold up, GLP-1s could open new frontiers in psychiatric treatment.
Risks and Opportunities
Despite their potential, GLP-1s carry risks. Their well-documented side effects include gastrointestinal issues such as nausea, vomiting, and diarrhea, while rare but serious risks include pancreatitis and gallbladder disease.
A major challenge is delivery. Most GLP-1s were developed for metabolic disorders, resulting in systemic circulation, peripheral side effects, and limited brain penetration.
To address these limitations, companies like Kariya are pioneering next-generation GLP-1s designed specifically for neurodegenerative diseases (15). These compounds aim to cross the blood-brain barrier more efficiently, reducing the need for broad systemic exposure and potentially improving both efficacy and safety. If successful, neuro-specific designs could overcome the limitations of repurposing metabolic GLP-1s and establish a new standard for neurotherapeutics. However, repurposed drugs still hold value in the short term due to their established safety profiles and extensive real-world data.
If successful, neuro-specific designs could overcome the limitations of repurposing metabolic GLP-1s and establish a new standard for neurotherapeutics
The broader issue is that we lack a full understanding of GLP-1’s underlying biochemical mechanisms. We don’t fully understand to what extent their neurological effects are a direct consequence of targeting brain-specific pathways or merely a downstream benefit of improved metabolic health. If primarily metabolic, their role may be more preventative than therapeutic.
The View from the Crow’s Nest
With major clinical trials underway, the next few years will be pivotal in determining whether GLP-1s truly have a place in neurology. Evidence supporting their cognitive benefits remains mixed—while some studies report improvements compared to placebo, others show no effect, underscoring the need for more rigorous investigation.
If semaglutide’s Phase III Alzheimer’s trials demonstrate even modest benefits, these results could reshape treatment paradigms. Meanwhile, research into PD, psychiatric disorders, and addiction suggests a potential for broader applications.
As pharmaceutical companies race to refine and expand this drug class, the competition between repurposed GLP-1s and neuro-specific designs may be the catalyst that unlocks their full potential in neurology—offering hope to millions awaiting better treatment options.
If you are interested in learning more, get in touch at strategy@spinnakerLS.com.
Spinnaker offers true partnership and comprehensive guidance to help leaders navigate the complexities of the Life Sciences industry and chart a path to success. From early-stage market assessment through commercial execution and ongoing lifecycle management, we deliver tailored solutions to ensure optimized practicable results.
Sources:
https://aaic.alz.org/releases-2024/glp-drug-liraglutide-may-protect-against-dementia.asp
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)02808-3/fulltext
https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(23)00378-2/abstract
https://www.sciencedirect.com/science/article/pii/S0376871624013498