Summary: Low, microdose lithium delivered in a brain-permeable formulation appears to stop progression of Alzheimer’s-related pathology and restore cognitive function in an animal model.
Source: McGill University
There is ongoing debate in the scientific community about lithium’s potential to treat Alzheimer’s disease. Conflicting results stem from widely varied study designs, formulations, dosing regimens, timing of treatment and experimental models. High, chronic lithium doses used for mood disorders also cause side effects that make long-term treatment difficult, particularly in older adults.
Researchers at McGill University, led by Dr. Claudio Cuello in the Department of Pharmacology and Therapeutics, report new evidence that a microdose lithium formulation which favors delivery to the brain can halt advanced Alzheimer’s-like pathology and recover cognition in a transgenic rat model. The dose used was up to 400 times lower than typical clinical lithium regimens for mood disorders. These findings are published in the Journal of Alzheimer’s Disease.
Building on earlier work
Dr. Cuello notes that the project advanced after graduate student Edward Wilson joined the team. Initial tests using conventional lithium formulations at doses comparable to clinical use produced rapid adverse effects in rats and were abandoned. The team then identified an encapsulated lithium formulation that had shown benefit in a Huntington’s disease model, and they tested that preparation in their Alzheimer’s-like transgenic rat model.
The McGill transgenic rat used in this research expresses human mutations linked to Alzheimer’s disease and develops hallmark features including progressive amyloid plaque accumulation and cognitive decline. Earlier work from the group showed that microdoses of lithium, administered at stages before plaque formation, produced positive outcomes and were reported in 2017 in Translational Psychiatry. Encouraged by those results, the researchers examined whether the same microdose formulation could be effective at later, post-plaque stages.
In the new experiments, microdoses of lithium were administered in a formulation designed to cross the blood-brain barrier while keeping systemic lithium levels very low, thereby minimizing the risk of adverse effects. Treatment given during later stages—comparable to early clinical or late preclinical Alzheimer’s when plaques are present and cognitive decline starts—produced measurable reductions in pathology and improvements in cognitive performance in the rat model.
Dr. Cuello emphasizes the practical implications: targeted microdose formulations that deliver lithium efficiently to the brain could offer immediate therapeutic potential while avoiding the toxicity associated with higher systemic doses. Although no treatment is likely to reverse extensive, established brain damage at advanced clinical stages, microdose therapy may provide meaningful benefit if applied in early or preclinical phases of Alzheimer’s disease.
Next steps and clinical outlook
Dr. Cuello describes two main pathways for follow-up research. One approach is to evaluate combination therapies that pair the microdose lithium formulation with other promising drug candidates; work in this direction is ongoing in collaboration with Dr. Sonia Do Carmo in his laboratory. The second approach is to initiate early-stage clinical trials to test the encapsulated microdose formulation in people who show signs of preclinical Alzheimer’s pathology or in high-risk populations, such as adults with Down syndrome who are genetically predisposed to Alzheimer’s disease.
While pharmaceutical investment in such trials has been limited, the authors are hopeful about finding partners to support clinical testing. If validated in humans, this strategy could offer a safer, disease-modifying option for slowing Alzheimer’s progression when started before irreversible damage occurs.
Source:
McGill University
Media Contacts:
Jason Clement – McGill University
Image Source:
The image is in the public domain.
Original Research: Open access
“NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats”. Wilson, Do Carmo, Cuello, et al.
Journal of Alzheimer’s Disease. DOI: 10.3233/JAD-190862.
Abstract (summary)
The study evaluates NP03, a microdose lithium formulation, in the McGill-R-Thy1-APP transgenic rat model during the transition from plaque-free to plaque-bearing stages. Rats received NP03 (40 μg Li/kg; 1 ml/kg body weight) for 12 weeks. Outcomes included remote working memory by novel object recognition, measurements of human Aβ38, Aβ40 and Aβ42, inflammatory mediators, thioflavin-S plaque staining, vesicular acetylcholine transporter (VAChT) bouton density, and markers of inflammation and oxidative stress. NP03 treatment rescued object recognition deficits, reduced loss of hippocampal cholinergic boutons, lowered soluble and insoluble cortical Aβ42, and decreased hippocampal plaque number. NP03 also reduced neuroinflammation and oxidative stress markers, indicating that microdose lithium can be effective after amyloid plaques appear.