Researchers are investigating whether glucagon-like peptide-1 receptor agonists (GLP-1 RAs), medications currently approved for obesity and type 2 diabetes, can be repurposed to treat Alzheimer’s disease (AD). While these drugs are used off-label for this purpose and a direct disease-modifying benefit in established AD remains unproven, emerging evidence suggests potential neuroprotective effects that extend beyond metabolic therapy, according to News Medical.
Mechanisms of Brain Health and Protection
GLP-1 receptors are densely expressed in the brain, specifically within the neocortex and hippocampus, as well as on cell bodies, dendrites, and presynaptic terminals, according to Cureus. This localization allows the drugs to potentially modulate synaptic transmission, neuronal excitability, and synaptic plasticity.
In experimental models, GLP-1 RAs have been linked to several neuroprotective mechanisms:
- Amyloid and Tau Reduction: Liraglutide and semaglutide have shown protective effects by reducing levels of tau protein and amyloid-beta (Aβ). Dulaglutide has also been found to reduce Aβ accumulation and tau phosphorylation in preclinical mouse models.
- Enzyme Regulation: In rat models where AD was induced using okadaic acid, liraglutide treatment reduced the levels of BACE1 (β-site amyloid precursor protein cleaving enzyme 1), which may limit the formation of amyloid plaques.
- Cellular Function: Liraglutide has been shown to increase insulin sensitivity and reduce BACE1 levels in SH-SY5Y human neuroblastoma cells. Additionally, GLP-1 RAs have been found to improve mitochondrial function and preserve the glucose metabolic rate.
- Signaling Pathways: Semaglutide, liraglutide, and exendin-4 have been experimentally linked to GSK3β phosphorylation and PI3K/AKT signaling, which may reduce neuroinflammation and tau hyperphosphorylation.
Preclinical Findings in Animal Models
Research in higher animal models indicates that prophylactic treatment with liraglutide before exposing monkeys to toxic Aβ proteins reduced neurodegeneration of brain synapses and the formation of abnormal tau protein. Exenatide produced similar effects, though they were less potent, according to News Medical.
Further supporting this potential, studies in mice revealed that the knockout of GLP-1 receptors resulted in reduced memory formation and synaptic plasticity.
Clinical Context and Unmet Needs
The investigation into GLP-1 RAs comes amid a growing global burden of neurodegenerative diseases. More than 55 million people worldwide live with dementia, the majority of whom have AD. In the United States, 7.2 million people aged 65 and older have the disease, with estimates projected to reach 13.8 million by 2060, according to Cureus.
Current treatment options for AD include NMDA receptor antagonists and cholinesterase inhibitors, which provide brief symptomatic cognitive improvement. Newer therapies such as donanemab and lecanemab target Aβ and report modest disease-modifying effects, but their safety and long-term outcomes are not yet known. Cureus reports that none of these current approaches are truly neurorestorative or neuroprotective, leaving a pressing unmet need in the field.
Challenges and Future Outlook
Despite encouraging results in experimental models, clinical trials have yielded mixed results regarding cognitive outcomes. Because GLP-1 RAs are approved for metabolic indications rather than AD, their use for cognitive decline remains investigational. Researchers continue to study whether these medications can move beyond their role in glucose homeostasis to become meaningful treatments for Alzheimer’s disease.
