The New Frontier in Neurological Research: Are GLP-1s Changing the Game?

Research to treat Alzheimer’s and other neurodegenerative diseases has been largely focused on removal of amyloid-beta plaques and tau tangles from the brains of individuals with the diseases. Most of the therapies that have recently received approval are targeted against the amyloid-beta and there is considerable excitement about the group of potential therapies aimed at treatment of neurodegenerative diseases through the route of metabolic dysfunction and inflammation. The majority of drugs aimed at treatment of neurodegenerative diseases that are in late stages of clinical testing are repurposed from use in other diseases. Most of the current repurposed potential therapies for neurodegenerative diseases are GLP-1 receptor agonists, currently used to treat type 2 diabetes and obesity. This review will cover the current GLP-1 receptor agonists or analogs that are currently in use for treatment of type 2 diabetes and the potential promise for use in treatment of various other neurological disorders. The review will also cover presentations given by several of these drugs at the American Academy of Neurology (AAN) 2023 Annual Meeting.

Conversations at AAN

The AAN also had a plenary session that was a debate on the hype of GLP-1’s as neuroprotectants and future hope for other neurological diseases.

As was previously mentioned, by analyzing the vast amount of real world data obtained from trials of neurodegenerative diseases that have already been conducted, we will discover a major paradigm shift in how we will be managing and treating neurodegenerative diseases using the GLP-1s. In order for us to proceed in this new direction, however, the GLP-1s must provide us with significant amounts of both clinical relevant as well as statistically significant data from the studies that are currently being conducted.

Why This Matters

There is strong evidence from large, long-term studies that the GLP-1s are highly efficacious for the treatment of type 2 diabetes and of obesity. There is also substantial real-world evidence of benefit in a number of other diabetes and obesity-related diseases. However, there is as yet no independent evidence of any benefit in the treatment of any of the neurological diseases.

There are three main metabolic actions of GLP-1s that explain their great value for non-neurological diseases primarily related to diabetes and obesity. First, there are central effects on appetite and satiety, second, there are peripheral actions on glucose metabolism, and third, there are gastric effects that influence gastric emptying. Importantly, there is no independent and clinically demonstrable effect of GLP-1s in neurological diseases. However, two Phase 3 trials were conducted, one for Parkinson’s disease and the other for Alzheimer’s disease, both of which were unsuccessful.

Recently in the treatment of of metabolic diseases (diabetes and obesity and GLP-1s) there has been a fundamental change in the approach to their treatment. As yet there is not the same evidence to support a similar major change in approach to other of the neurological diseases.

Beyond Blood Sugar

Most people are familiar with the GLP-1 receptor agonists as treatments for type 2 diabetes and obesity. They have a wide range of effects in the body and as a result have been used to treat a wide variety of diseases, such as cardiovascular disease, kidney disease, and osteoarthritis. However, in recent years studies have found that GLP-1 receptor agonists have effects in the brain and may be used to treat a variety of neurological diseases. Most research has focused on Parkinson’s disease and Alzheimer’s disease with two Phase 3 trials assessing the use of GLP-1 receptor agonists in Alzheimer’s disease. Both of these trials failed to meet their primary endpoints.

The GLP-1 receptor is found in memory and learning centers of the brain. GLP-1 is known to decrease blood sugar and cause feelings of satiety which is why it is used as a medication for type 2 diabetes and obesity. Alzheimer’s is considered to be a ‘brain energy failure’ or ‘Type 3 diabetes’ because the brain fails to properly utilize glucose for energy.

• Combating Neuroinflammation: One of the most critical roles of GLP-1s in the brain is to reduce the overactivation of microglia and astrocytes. When these immune cells remain in a chronic inflammatory state, they damage healthy neurons. GLP-1 agonists help “quiet” this inflammatory storm.
• Protecting the Neurovascular Unit (NVU): The health of the brain depends on a functional blood-brain barrier and steady blood flow. GLP-1s have been shown to improve the integrity of the NVU, promoting better microcirculation and protecting the brain’s delicate vascular network from the damage seen in early-stage Alzheimer’s.
• Enhancing Neuronal Survival: These drugs appear to stimulate the production of new neurons (neurogenesis) and protect existing synapses—the vital connections that allow brain cells to communicate.
• Reducing Toxic Proteins: Beyond metabolic benefits, GLP-1 agonists have demonstrated the ability to reduce the accumulation of amyloid-beta and phosphorylated tau in animal models, suggesting they may hit the traditional targets of Alzheimer’s treatment while simultaneously addressing metabolic health.

Who It Affects

A Wider Net for Treatment

A Wider Net for Treatment

1. People with Early-Stage Alzheimer’s and MCI

Semaglutide for Early-Stage Alzheimer’s Disease or Mild Cognitive Impairment (MCI) – The EVOKE and EVOKE+ Phase 3 Clinical Studies for Alzheimer’s.

2. Individuals with Vascular Comorbidities

Another study arm for the small number of participants with evidence of small-vessel disease of the brain will explore the effects of semaglutide in these individuals with Alzheimer’s disease whose brain changes are ‘accelerated’ by poor heart or circulatory health. As GLP-1s have powerful effects to improve the health of blood vessels and to increase blood flow to tissues, they may have a particular role in individuals with vascular comorbidities.

3. Patients with Metabolic Syndrome

Research shows that in people with Type 2 Diabetes who are on GLP-1s for diabetes, GLP-1s decrease the risk of Alzheimer’s by as much as 30% more than any other diabetes treatment. Since so many people with Alzheimer’s also have metabolic disorders such as Type 2 Diabetes and are obese, it makes sense that a single drug could have a dual benefit in these people.

4. Managed Care & Payer Implications

Although expensive, semaglutide and other GLP-1s have the potential to be more cost effective for Alzheimer’s disease treatment than most currently used biologic agents, for a large patient population.

- Redefining “Early Intervention” Off-Label and Formulary Control: At present, a very large volume of GLP-1s are prescribed for weight loss at great cost to the pharmacy. In the T2D indication for which they are approved, PA is very common in order to prevent leakage for off-label use for cognitive protection prior to FDA approval for that indication. Long-Term Claims Experience — The health and life insurer will need to assess the future impact of GLP-1s on metabolic processes outside of the central nervous system as well as the CNS and the impact on future mortality and morbidity in terms of long-term care claims as well as inpatient claims for treatment of complications of advanced dementia. What Changes The Metabolic-Neurological Link The link between metabolic diseases and neurodegenerative diseases of the brain, or the Metabolic-Neurological Link, is due in large part to the fact that most individuals with metabolic diseases are also in an state of insulin resistance. This means that even in the absence of Type 2 Diabetes, an individual with metabolic syndrome is in a state that puts them at risk for a variety of neurodegenerative diseases of the brain. In order to understand how the insulin resistant state of metabolic diseases can lead to a variety of different neurodegenerative diseases, it is first necessary to have an understanding of the role that the peptide insulin plays in metabolism of glucose outside of the brain and in the brain itself. Outside of the brain, insulin is a 5-kD peptide secreted by the pancreas that allows glucose to enter into cells. Within the brain, the same signaling system that is used for metabolism of glucose in the periphery is used for bioenergetics, for maintaining healthy synapses, for promoting the growth of new dendritic spines, for proteostasis or the balance of protein synthesis to protein degradation, for clearing amyloid-beta from the brain to prevent the development of Alzheimer’s dementia, and for the phosphorylation of tau protein to prevent the development of dementia caused by tau protein. Importantly, the signaling system for insulin also modulates a number of vascular functions including inflammation and vasoreactivity. Because of the role that the insulin signaling system plays in so many different functions within the brain, it is not surprising that decreased levels of the peptide insulin or impaired function of the insulin signaling system have been implicated in a variety of neurodegenerative diseases of the brain. As a result, a number of investigators are currently exploring ways to increase or enhance the function of cerebral insulin in a number of different neurodegenerative diseases. A Shift in the Treatment Paradigm Three Changes Occurring in Alzheimer’s Treatment, a Neurodegenerative Disease of the Brain, Because of the Introduction of GLP-1s Into This Field of Study. From Single-Target to Combination Therapies Like many cancer and HIV treatments, Alzheimer’s disease will likely be treated with a cocktail of drugs. So while an anti-amyloid drug can clear plaques in the brain, it is likely that such a patient will also be prescribed GLP-1s in order to decrease inflammation, and to increase brain metabolism. Faster Access Through Repurposing Many GLP-1 receptor agonists such as semaglutide (Ozempic, Wegovy) and liraglutide (Victoza) are already FDA-approved for and commonly prescribed for Type 2 Diabetes (T2D). This is why they will most likely enter the neurodegenerative space much sooner than any other new drugs on the market. In addition, the safe profile of use of these already well established GLP-1 receptor agonists for T2D is well known by physicians and therefore their use off-label will be more acceptable. A Renewed Focus on Brain Health Maintenance The potential for the GLP-1 receptor agonists to be used for the treatment of Alzheimer’s disease will, in part, reinforce the view that the best strategy for the prevention of and the treatment of Alzheimer’s disease, a disease of the brain, is through the treatment and the prevention of Alzheimer’s disease, and will increasingly focus on maintaining a healthy brain through the treatment and the maintenance of the overall health of the rest of the body (metabolic health, blood pressure, weight, etc.). Looking Ahead: What Patients Should Know Now The Alzheimer’s Association and many researchers within the medical field today are following the results of several Phase 3 studies currently in progress to see if the data generated from the use of GLP-1 receptor agonists for the treatment of Type 2 diabetes translates to the promised potential of GLP-1s to prevent or delay the onset of Alzheimer’s disease. In summary, the GLP-1 receptor agonists hold considerable promise in the management and perhaps even prevention of Alzheimer’s disease. They are targeting some of the causes of the neurodegenerative process for the first time. References - Payors must determine if they will cover these drugs at the Mild Cognitive Impairment (MCI) stage. Because dementia develops over decades, managed care organizations like the Academy of Managed Care Pharmacy (AMCP) are already launching initiatives to assess dementia risk in adults aged 40 to 60. - Don’t Self-Medicate: Current GLP-1 dosages and formulations approved for weight loss or diabetes may not be the same as those required for effective brain protection. - Safety First: While generally well-tolerated, these drugs can have side effects, primarily gastrointestinal, and their long-term impact on the brain is still being mapped. - Participate in Research: The fastest way to bring these treatments to those who need them is through clinical trials. Services like TrialMatch can connect families with local studies. 1. Athauda D, Greig NH, Meissner WG, Foltynie T, Gandhi S. The promise of GLP-1 receptor agonists for neurodegenerative diseases. J Clin Invest. 2026;136(4):e194745. Published 2026 Feb 16. doi:10.1172/JCI194745 2. Banerjee M, Pal R, Mukhopadhyay S, Nair K. GLP-1 Receptor Agonists and Risk of Adverse Cerebrovascular Outcomes in Type 2 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Clin Endocrinol Metab. 2023;108(7):1806-1812. doi:10.1210/clinem/dgad076 3. Monti G, Gomes Moreira D, Richner M, Mutsaers HAM, Ferreira N, Jan A. GLP-1 Receptor Agonists in Neurodegeneration: Neurovascular Unit in the Spotlight. Cells. 2022;11(13):2023. Published 2022 Jun 25. doi:10.3390/cells11132023 4. AbuAlrob MA, Itbaisha A, Abujwaid YK, Abulehia A, Hussein A, Mesraoua B. Exploring the neuroprotective role of GLP-1 agonists against Alzheimer’s disease: Real-world evidence from a propensity-matched cohort. J Alzheimers Dis Rep. 2025;9:25424823251388650. Published 2025 Oct 16. doi:10.1177/25424823251388650 5. https://www.alz.org/blog/2025/glp-1s-and-alzheimer-s-what-you-need-to-know 6. Gandhi A, Parhizgar A. GLP-1 receptor agonists in Alzheimer’s and Parkinson’s disease: endocrine pathways, clinical evidence, and future directions. Front Endocrinol (Lausanne). 2025;16:1708565. Published 2025 Nov 20. doi:10.3389/fendo.2025.1708565 7. Kellar D, Craft S. Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches. Lancet Neurol. 2020;19(9):758-766. doi:10.1016/S1474-4422(20)30231-3 8. Cummings JL, Atri A, Feldman HH, et al. evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer’s disease. Alzheimers Res Ther. 2025;17(1):14. Published 2025 Jan 8. doi:10.1186/s13195-024-01666-7