[ExI] Low-dose lithium stops disease progression in a transgenic rat model of Alzheimer's disease

[Stuart LaForge]

This looks encouraging, since lithium is already a drug prescribed for  
mood disorders and the dosage for Alzheimer's is much lower than the  
currently used dosage. Of course they still need to conduct human  
clinical trials for efficacy. But hope is hope.

Stuart LaForge


https://scitechdaily.com/low-dose-lithium-may-stop-alzheimers-disease-in-its-tracks/

There remains a controversy in scientific circles today regarding the  
value of lithium therapy in treating Alzheimer’s disease. Much of this  
stems from the fact that because the information gathered to date has  
been obtained using a multitude of differential approaches,  
conditions, formulations, timing and dosages of treatment, results are  
difficult to compare. In addition, continued treatments with high  
dosage of lithium render a number of serious adverse effects making  
this approach impracticable for long term treatments especially in the  
elderly.

In a new study, however, a team of researchers at McGill University  
led by Dr. Claudio Cuello of the Department of Pharmacology and  
Therapeutics, has shown that, when given in a formulation that  
facilitates passage to the brain, lithium in doses up to 400 times  
lower than what is currently being prescribed for mood disorders is  
capable of both halting signs of advanced Alzheimer’s pathology such  
as amyloid plaques and of recovering lost cognitive abilities. The  
findings are published in the most recent edition of the Journal of  
Alzheimer’s Disease.

Building on their previous work
“The recruitment of Edward Wilson, a graduate student with a solid  
background in psychology, made all the difference,” explains Dr.  
Cuello, the study’s senior author, reflecting on the origins of this  
work. With Wilson, they first investigated the conventional lithium  
formulation and applied it initially in rats at a dosage similar to  
that used in clinical practice for mood disorders. The results of the  
initial tentative studies with conventional lithium formulations and  
dosage were disappointing however, as the rats rapidly displayed a  
number of adverse effects. The research avenue was interrupted but  
renewed when an encapsulated lithium formulation was identified that  
was reported to have some beneficial effects in a Huntington disease  
mouse model.

Lithium in doses up to 400 times lower than what is currently being  
prescribed for mood disorders is capable of both halting signs of  
advanced Alzheimer’s pathology such as amyloid plaques and of  
recovering lost cognitive abilities.

The new lithium formulation was then applied to a rat transgenic model  
expressing human mutated proteins causative of Alzheimer’s, an animal  
model they had created and characterized. This rat develops features  
of the human Alzheimer’s disease, including a progressive accumulation  
of amyloid plaques in the brain and concurrent cognitive deficits.


Microdoses of lithium at concentrations hundreds of times lower than  
applied in the clinic for mood disorders were administered at early  
amyloid pathology stages in the Alzheimer’s-like transgenic rat. These  
results were remarkably positive and were published in 2017 in  
Translational Psychiatry and they stimulated us to continue working  
with this approach on a more advanced pathology,” notes Dr. Cuello.

Encouraged by these earlier results, the researchers set out to apply  
the same lithium formulation at later stages of the disease to their  
transgenic rat modeling neuropathological aspects of Alzheimer’s  
disease. This study found that beneficial outcomes in diminishing  
pathology and improving cognition can also be achieved at more  
advanced stages, akin to late preclinical stages of the disease, when  
amyloid plaques are already present in the brain and when cognition  
starts to decline.

“From a practical point of view our findings show that microdoses of  
lithium in formulations such as the one we used, which facilitates  
passage to the brain through the brain-blood barrier while minimizing  
levels of lithium in the blood, sparing individuals from adverse  
effects, should find immediate therapeutic applications,” says Dr.  
Cuello. “While it is unlikely that any medication will revert the  
irreversible brain damage at the clinical stages of Alzheimer’s it is  
very likely that a treatment with microdoses of encapsulated lithium  
should have tangible beneficial effects at early, preclinical stages  
of the disease.”

Moving forward
Dr. Cuello sees two avenues to build further on these most recent  
findings. The first involves investigating combination therapies using  
this lithium formulation in concert with other interesting drug  
candidates. To that end he is pursuing opportunities working with Dr.  
Sonia Do Carmo, the Charles E. Frosst-Merck Research Associate in his  
lab.

He also believes that there is an excellent opportunity to launch  
initial clinical trials of this formulation with populations with  
detectable preclinical Alzheimer’s pathology or with populations  
genetically predisposed to Alzheimer’s, such as adult individuals with  
Down Syndrome. While many pharmaceutical companies have moved away  
from these types of trials, Dr. Cuello is hopeful of finding  
industrial or financial partners to make this happen, and, ultimately,  
provide a glimmer of hope for an effective treatment for those  
suffering from Alzheimer’s disease.

Reference: “NP03, a Microdose Lithium Formulation, Blunts Early  
Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like  
Transgenic Rats,” by Edward N. Wilson, Sonia Do Carmo, Lindsay A.  
Welikovitch, Hélène Hall, Lisi Flores Aguilar, Morgan K. Foret, M.  
Florencia Iulita, Dan Tong Jia, Adam R. Marks, Simon Allard, Joshua T.  
Emmerson, Adriana Ducatenzeiler and A. Claudio Cuello,  16 December  
2019. Journal of Alzheimer’s disease.
DOI: 10.3233/JAD-190862