A groundbreaking study from the Centre for Addiction and Mental Health (CAMH), Canada’s largest mental health research institution, has revealed that an experimental drug, GL II 73, may be capable of restoring memory and cognitive function in Alzheimer’s disease, a discovery that could reshape the future of dementia treatment. Published in Neurobiology of Aging, the study demonstrates that the novel compound not only improves memory deficits but also reverses brain cell damage in a mouse model of Alzheimer’s disease.
Alzheimer’s disease, the most common cause of dementia, currently affects over 55 million people worldwide, a number projected to rise to 78 million by 2030 and 139 million by 2050, according to the World Health Organization and Alzheimer’s Disease International. The disease imposes an immense global health and economic burden, with annual costs exceeding one trillion US dollars. Despite decades of research, most available treatments offer only modest symptom control, leaving an urgent unmet need for therapies that can truly halt or reverse the disease process.
Presently approved drugs, such as cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the NMDA receptor antagonist memantine, primarily provide temporary symptomatic relief, improving cognition or delaying functional decline for a limited period. Recently approved disease modifying agents targeting beta amyloid, including aducanumab and lecanemab, aim to slow disease progression, but their benefits remain modest and do not reverse existing cognitive loss. Against this backdrop, GL II 73 represents a potentially transformative approach focused on neural restoration rather than amyloid reduction.
GL II 73 functions as a positive allosteric modulator of α5 GABA A receptors. By enhancing GABAergic signaling in the hippocampus and prefrontal cortex, key regions involved in memory and learning, it restores inhibitory balance, reduces neuronal hyperexcitability, and promotes synaptic and dendritic spine integrity. This mechanism targets fundamental network dysfunction underlying cognitive decline in Alzheimer’s, distinguishing it from current drugs that primarily address downstream pathology.
The CAMH study builds on more than a decade of research from the institute’s Neurobiology of Depression and Aging Program. Using genetically modified mice that develop Alzheimer’s like beta amyloid buildup, researchers tested the drug across both early and advanced disease stages. In younger mice with early pathology, a single dose of GL II 73 completely reversed memory deficits, restoring performance to healthy control levels. In older mice with more advanced disease, continuous treatment over four weeks yielded measurable cognitive improvement, though less pronounced, indicating partial recovery even in later stages of pathology.
Unlike existing Alzheimer’s drugs that target amyloid plaques or tau tangles, GL II 73 acts through selective modulation of hippocampal GABA receptors to repair neural circuitry and restore functional connectivity. Preliminary evidence also suggests the compound could have applications in other disorders marked by cognitive dysfunction, such as depression, epilepsy, and schizophrenia.
Experts believe the findings could mark the beginning of a paradigm shift in Alzheimer’s management, from symptomatic control to true neural repair. However, researchers caution that the results, while promising, are based on preclinical models. Rigorous human trials will be necessary to evaluate the safety, dosage, and long-term efficacy of GL II 73 before it can enter clinical use.
If successfully translated to humans, GL II 73 could become the first therapy capable of not just slowing but potentially reversing cognitive deterioration, offering renewed hope to millions of patients and families grappling with the devastating impact of Alzheimer’s disease worldwide.
References
- Bernardo AM, Marcotte M, Wong K, Sharmin D, Pandey KP, Cook JM, Sibille EL, Prevot TD. Procognitive and neurotrophic benefits of α5-GABA-A receptor positive allosteric modulation in a β-amyloid deposition mouse model of Alzheimer’s disease pathology. Neurobiol Aging. 2025 Mar;147:49-59.
- Waite LM. New and emerging drug therapies for Alzheimer disease. Aust Prescr. 2024 Jun;47(3):75-79.
- Zhang, J., Zhang, Y., Wang, J. et al. Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies. Sig Transduct Target Ther 9, 211 (2024). https://doi.org/10.1038/s41392-024-01911-3
- https://www.nature.com/articles/s41392-024-01911-3?utm_source=chatgpt.com
- McCoy AM, Prevot TD, Sharmin D, Cook JM, Sibille EL, Lodge DJ. GL-II-73, a Positive Allosteric Modulator of α5GABAA Receptors, Reverses Dopamine System Dysfunction Associated with Pilocarpine-Induced Temporal Lobe Epilepsy. Int J Mol Sci. 2023 Jul 18;24(14):11588.