GLP-1 Agonists as Therapeutics for Alzheimer's Disease: Not Right Now, but Maybe in the Future

Alzheimer Disease (AD) is an age-related neurodegenerative disorder currently affecting over 7 million people in the United States.¹ About 1 in 9 patients aged 65 and older has AD, with most patients being female. AD patients demonstrate progressive declines in cognition and communication, as well as changes in behavior. In later stages of this disease, difficulty in walking, speaking, and swallowing are also observed.

Pathophysiology and Management of AD

The pathophysiology of AD is thought to result from the buildup of amyloid-beta plaques and tau (T) neurofibrillary tangles, leading to neuroinflammation, synaptic dysfunction, with eventual neuronal death and brain atrophy.^2,3 Cholinergic insufficiency, mitochondrial dysfunction, excitotoxicity, and defective autophagy further contribute to the disease progression.^4-7

There is no cure for AD. Management focuses on slowing disease progression and relieving the symptoms of mood changes with antidepressants and antipsychotics. A careful assessment of drug dosage, indications, and adverse effects is critical to treating elderly patients with behavioral symptoms. Three major drug classes currently approved for AD include:

• Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine), which prevent the breakdown of acetylcholine to address the cholinergic deficiency associated with AD pathology.⁸ While donepezil is indicated for all stages of AD, rivastigmine and galantamine only manage the mild and moderate stages of the disease.
• Memantine is often added in the moderate-to-severe stages of AD. This uncompetitive antagonist of the NMDA receptor for glutamate reduces neuron loss and disease symptoms by allowing restoration of damaged neurons.^7,8 Combination treatment of memantine and donepezil in moderate to severe AD has been observed to reduce disease progression, with tolerable adverse effects.⁹
• Anti-amyloid drugs (lecanemab and donanemab) are intravenous infusions recently approved for MCI or mild dementia. However, the patient must meet specific criteria to be candidates for therapy, including diagnostic tests to detect the presence of amyloid, and frequent MRIs during therapy to monitor for the possibility of brain hemorrhage (ARIA).¹⁰ Lecanemab is infused every 2 weeks, while donanemab is administered monthly. Both drugs require the patient to be in a specialized infusion clinic for drug administration.

GLP-1 Agonists and Neuroprotection: Present and Future Studies

Glucagon-like peptide 1 (GLP-1) agonists remain popular as weight-loss medications. Satiety is promoted by activation of hypothalamic GLP-1 receptors, along with reduced gastric emptying. These agents, also known as incretins, manage insulin resistance in type II diabetes by enhancing insulin release from the pancreas while inhibiting glucagon. Taken together, there is support for the use of these drugs to reduce both cardiovascular and renal events.¹¹

As type 2 diabetes and obesity are included as possible risk factors for AD, the neuroprotective role of GLP-1 agonists has been studied, with several possible mechanisms elucidated in animal models. These include reductions in inflammation and oxidative stress, as evidenced by decreased inflammatory markers and increased brain antioxidant defenses.¹²

However, recent results from phase 3 clinical trials (4000 patients with early AD were provided with daily oral semaglutide for approximately 2 years) did not meet expectations for the use of GLP-1 agonists as another therapeutic option for AD at this time. This may be because semaglutide was unable to cross the brain at a dosage that could enhance neuroprotection. It was also unclear how far the patients in the clinical trial had progressed in the neurodegenerative process after starting oral semaglutide.¹³ Future studies will evaluate if newer dual and triple agonists, or small-molecule oral GLP-1 agonists, have enhanced penetration through the brain to reduce neurodegeneration.¹⁴ This can include the use of alternate routes of administration (intranasal) or the use of drug nanoparticles (15). Additionally, the patients with the greatest potential to benefit from the neuroprotection afforded by these drugs should be identified.¹⁵ Lastly, clinical trials should evaluate if incretins combined with other medications can enhance efficacy, with minimal drug interactions and adverse effects.¹⁵

REFERENCES

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10. Ramanan VK, Armstrong MJ, Choudhury P, et al. Antiamyloid Monoclonal Antibody Therapy for Alzheimer Disease: Emerging Issues in Neurology. Neurology. 2023;101(19):842-852. doi:10.1212/WNL.0000000000207757

11. Yan H, Karthikeyan H, Fan W, Yang Q, Wong ND. U.S. Eligibility and Preventable Cardiovascular, Diabetes, and Kidney Outcomes from Semaglutide in the SELECT Trial. JACC Adv. 2025;4(6 Pt 2):101773. doi:10.1016/j.jacadv.2025.101773.

12. Du H, Meng X, Yao Y, Xu J. The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer's disease. Front Endocrinol (Lausanne). 2022; 13:1033479. Published 2022 Nov 17. doi:10.3389/fendo.2022.1033479.

13. Rosen M. (2025, December 8) GLP-1 drugs failed to slow Alzheimer’s in two big clinical trials. Science News. Accessed January 12, 2026. https://www.sciencenews.org/article/glp-1-drugs-failed-slow-alzheimers

14. Mohammed O, Kelemu T. Incretin-Based Therapies in Alzheimer's and Parkinson's Disease: Advancing Neuroprotection with Dual and Triple Agonists-A Review. Health Sci Rep. 2025;8(7): e71065. Published 2025 Jul 15. doi:10.1002/hsr2.71065.

15. Zhou ZD, Yi L, Popławska-Domaszewicz K, Chaudhuri KR, Jankovic J, Tan EK. Glucagon-like peptide-1 receptor agonists in neurodegenerative diseases: Promises and challenges. Pharmacol Res. 2025; 216:107770. doi: 10.1016/j.phrs.2025.107770.