GLP-1 Receptor Agonists Show Translational Potential in Alzheimer Disease Despite Mixed Study Results

Researchers recently presented a living systematic review of studies assessing glucagon-like peptide-1 (GLP-1) receptor agonists, including liraglutide (Victoza; Novo), semaglutide (Ozempic; Novo Nordisk), and exenatide (Byetta; Eli Lilly), for the treatment of Alzheimer disease (AD) and mild cognitive impairment (MCI). Initial findings from the analysis showed that these agents demonstrated signals of neuroprotection and a reduced incidence of dementia, suggesting potential for disease-modifying effects.¹

Across more than 2000 participants with mild to moderate AD syndrome with no diabetes, liraglutide was administered as a daily subcutaneous injection over 12 months in the phase 2b ELAD trial (NCT01843075). Results showed that the treatment with liraglutide was associated with attenuation of FDG-PET decline and reduced hippocampal atrophy (standardized change, approximately 0.25 SD; P ≈ .04), despite not meeting its primary outcome, change in cerebral glucose metabolic rate.²

Presented at the 2026 American Academy of Neurology (AAN) Annual Meeting, held April 18–22 in Chicago, Illinois, this review integrated phase 2/3 trials and large real-world studies between 2000 to 2025 evaluating GLP-1 receptor agonists to assess clinical efficacy, biomarker outcomes, safety, and accessibility in AD. Led by Aditya Jain, MBBS, postgraduate resident in the Department of Surgery at Shyam Shah Medical College in India, the study compared trial findings with population-level dementia risk reduction and applied an Efficacy–Feasibility Matrix to evaluate translational readiness for scalable, disease-modifying use.

Semaglutide, evaluated as a once-daily oral therapy in the EVOKE (NCT04777396) and EVOKE+ trials (NCT04777409), had the largest statistical power among the agents studied, with approximately 1800 participants per trial. However, results reported in November 2025 showed that the agent did not demonstrate superiority over placebo in reducing disease progression in patients with early-stage symptomatic AD, despite improvements observed in AD-related biomarkers.³

READ MORE: Semaglutide Modulates CSF Immune Cell Activity and Reduces AD Tau Biomarkers in Phase 3 Substudy

Exenatide, delivered weekly by subcutaneous injection, remained underpowered because of an early termination and did not demonstrate significant effects in a phase 2 trial (NCT01255163) among patients with high probability AD.⁴ Additional findings showed that real-world studies of more than 2 million individuals with diabetes, GLP-1 receptor agonist use was consistently associated with an approximately 20% to 35% lower incidence of dementia compared with DPP-4 inhibitors or SGLT2 inhibitors, with the strongest associations observed for semaglutide.

Translational assessments categorized GLP-1 receptor agonists as having high efficacy but moderate feasibility, reflecting strong biological rationale alongside practical limitations, including cost and the need for injectable administration for certain agents. Authors also noted that safety findings were consistent with known metabolic indications, with gastrointestinal adverse events occurring in more than 10% of patients and no observed central nervous system toxicity.

Using an Efficacy–Feasibility Matrix, findings suggested that semaglutide may offer advantages for clinical application, particularly because of its oral formulation and potential for broader scalability. GLP-1 receptor agonists, initially developed for the treatment of diabetes and obesity, have demonstrated the ability to cross the blood-brain barrier and influence insulin signaling, neuroinflammatory processes, and amyloid and tau–related pathways. These combined metabolic and neurobiological effects have led to their consideration as potential repurposed therapeutic candidates for AD.

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REFERENCES
1. Jain A, Narsinghpura A, Mallepally A, et al. GLP-1 Receptor Agonists in Alzheimer’s Disease: A Living Systematic Review Integrating Clinical Trials, Real-world Evidence, and Translational Feasibility. Presented at: 2026 AAN Annual Meeting; April 18-22; Chicago, Illinois.
2. Edison P, Femminella GD, Ritchie C, et al. Liraglutide in mild to moderate Alzheimer's disease: a phase 2b clinical trial. Nat Med. 2026;32(1):353-361. doi:10.1038/s41591-025-04106-7
3. Novo Nordisk A/S: Evoke phase 3 trials did not demonstrate a statistically significant reduction in Alzheimer's disease progression. News release. Novo Nordisk. November 24, 2025. Accessed April 20, 2026. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916462
4. Mullins RJ, Mustapic M, Chia CW, et al. A Pilot Study of Exenatide Actions in Alzheimer's Disease. Curr Alzheimer Res. 2019;16(8):741-752. doi:10.2174/1567205016666190913155950