2026 ECNP Congress

PS03-3146

Neuroprotective potential of Glucagon-like peptide-1 receptor agonists in Alzheimer’s disease: evidence from preclinical animal studies

Tuba Ergun — E.B. Polat, H.K. Elçioğlu · Institute of Health Sciences- Marmara University, Department of Pharmacology, Istanbul, Türkiye

2026 ECNP Congress

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), initially approved for the treatment of type 2 diabetes mellitus (T2DM), have recently gained prominence as potential neuroprotective agents in the management of Alzheimer’s disease (AD) [1]. T2DM has been linked with an increased risk of AD, supporting the concept of type 3 diabetes mellitus, in which brain insulin resistance contributes to neurodegeneration. GLP-1 is synthesized in intestinal enteroendocrine L cells peripherally. It is also synthesized and released locally by neurons in the nucleus tractus solitarius. GLP-1 binds to GLP-1 receptors located on neurons and glial cells within the central nervous system, abundantly expressed in the hypothalamus and cerebral cortex. GLP-1RAs cross the blood-brain barrier and modulate important pathological processes such as tau phosphorylation, amyloid-β accumulation and neuroinflammation, resulting in improved cognitive outcomes in animal models [2]. GLP-1 has been reported to reduce amyloid-β accumulation and tau hyperphosphorylation through the PI3K/Akt pathway activation and glycogen synthase kinase-3β inhibition [1]. This review aims to conclude current preclinical animal studies on the neuroprotective effects of GLP-1RAs in AD. A literature-based review was conducted focusing on preclinical animal studies. Animal studies included in this review have investigated GLP-1RAs in AD using transgenic mouse and rat models such as APP/PS1, 5xFAD and 3×Tg as well as chemically induced models including streptozotocin- and amyloid-β-induced rodents. In these models, liraglutide has been shown to reduce amyloid-β plaque accumulation, attenuate tau hyperphosphorylation and improve synaptic plasticity, neurogenesis, and cognitive function. These observed effects were associated with reduced microglial activation, as indicated by decreased ionized calcium-binding adaptor molecule 1 expression in transgenic AD models. In addition, liraglutide has been associated with reduced oxidative stress and improved mitochondrial function as reflected by malondialdehyde and superoxide dismutase biomarkers [3]. Similarly, it has been indicated that exenatide may attenuate amyloid-β levels, suppress neuroinflammatory responses through the nuclear factor kappa B pathway, and restore impaired insulin signaling and mitochondrial function, as evidenced by reduced insulin receptor substrate-1 phosphorylation across multiple experimental models [3,4]. Furthermore, lixisenatide has been shown to enhance long-term potentiation in rat models [3]. Moreover, other GLP-1RAs such as dulaglutide and semaglutide have demonstrated reductions in amyloid and tau pathology with improvements in neuronal survival, although some studies reported no significant effects on plaque formation [3–5]. Overall, GLP-1RAs exert neuroprotective effects in preclinical animal models of AD through multiple mechanisms, including reductions in amyloid-β and tau pathology, attenuation of neuroinflammatory responses, reduced oxidative stress, and improvement of insulin signaling. These findings support the use of GLP-1RAs as potential neuroprotective strategies. However, the present clinical evidence remains inadequate to confirm their therapeutic efficacy in humans, which calls for further well-designed clinical studies. The purpose of this review is to synthesize current preclinical animal studies to date on the neuroprotective effects of GLP-1RAs in AD.

References

  1. Au, H.C.T., Lam, P.H., Lim, P.K., McIntyre, R.S., 2025. Role of glucagon-like peptide-1 on amyloid, tau, and α-synuclein: target engagement and rationale for development in neurodegenerative disorders. Neuroscience and Biobehavioral Reviews 173, 106159.
  2. O’Mara, A., Mody, B.P., Mammi, M., Simjian, T., Ghattas, K., Kaliki, S., Le, N.P.M., Liew, A., Migliore, M., Mekary, R.A., 2026. The effect of GLP-1 receptor agonists on cognition in nondiabetic patients with mild cognitive impairment or Alzheimer’s disease: a meta-analysis of randomized controlled trials. Neurological Sciences 47(1), 149.
  3. Kong, F., Wu, T., Dai, J., Zhai, Z., Cai, J., Zhu, Z., Xu, Y., Sun, T., 2023. Glucagon-like peptide-1 receptor agonists in experimental Alzheimer’s disease models: a systematic review and meta-analysis of preclinical studies. Frontiers in Pharmacology 14, 1205207.
  4. Corcoran, E., Kettlety, M., Mogul, U., Azah, J.N., Cork, S.C., 2026. The effects of GLP-1 receptor agonists on Alzheimer’s pathophysiology: a systematic review. Molecular and Cellular Neurosciences, in press.
  5. Du, H., Meng, X., Yao, Y., Xu, J., 2022. The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer’s disease. Frontiers in Endocrinology 13, 1033479.