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.
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 modelling 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.”
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.
“NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats,” by Wilson, Do Carmo, Cuello, et al. was published online on December 16, 2019 in the Journal of Alzheimer’s Disease.
Alzheimer’s Disease (AD) is a chronic neurodegenerative disease that typically occurs in those aged 65 years and older . It presents with a broadly related pathophysiology as Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease. AD is a senile dementia with its pathology occurring up to 18 years before its definitive diagnosis . In 2017, the Alzheimer’s association published a 2017 Facts and Figures report indicating that approximately 5.5 million people in America have Alzheimer’s and of those 5.5 million, 5.3 million are 65 years of age or older. Additionally, by 2050, the number of people that have Alzheimer’s may triple. The report also shows that, between 2000 and 2014, the death rate of Alzheimer’s has increased by 89%, by contrast, other public health conditions such as stroke and HIV have observed a 14% and 54% death rate decline, respectively.
AD and other types of dementia are characterized by a loss of ability to solve problems or maintain emotional control. Individuals with dementia experience personality changes and behavioral problems such as agitation and impaired intellectual functioning that interfere with normal activities and relationships. Dementia also generates hallucinations and delusions.
There are currently only a few FDA-approved treatments for AD, which belong to two classes of drugs: Acetyl cholinesterase Inhibitors (AChEI) and N-methyl-D-aspartic Acid (NMDA) antagonists. These treatments have been used for treating the symptoms of cognitive decline and language deficits and do not slow down or stop the progression of the disease. A drug that cures or at least slows down the disease is necessary, as Alzheimer’s is becoming pandemic.
Here we review select aspects of the AD pathogenesis, focusing on iron homeostasis and oxidative stress, dysregulation of the APP translation and processing, Amyloid-beta (Aβ) deposition, the proinflammatory cytokine Interleukin-1 beta (IL-1β), tau protein hyperphosphorylation and reduced neurogenesis. Moreover, we address a few compounds that provide alternatives to the current FDA approved drugs and target many different components and pathways of AD.
Current Small Molecule Treatments for AD
There are currently two classes of drugs that are used to treat the symptoms of AD: Acetylcholinesterase Inhibitors (AChEI) and N-Methyl-D-Aspartate (NMDA) receptor antagonists . Acetylcholinesterase (AChE) is an enzyme which degrades acetylcholine (ACh) in the synapse . The drugs that belong to the AChEI class are donepezil, rivastigmine and galantamine.
Decreased ACh in the AD brain has been well documented and evidence suggests that an AD-associated lowering of ACh activity in the basal forebrain leads to compromise of executive functions, ACh plays a role in certain cognitive abilities such as attention [83–86]. Studies also show a decrease in AChE activity in AD patients and that AChEI’s can reduce IL-1β and increase interleukin-4 (IL-4) [87,88]. There are several reviews on how AChE inhibitors work by arresting the activity of AChE, thus leading to increases in Ach [89–91].
By comparison, NMDA receptor antagonists are used to treat the toxic increases in Glutamate (Glu) within the brain . Glu excitotoxicity has been hypothesized to play a pivotal role in AD pathology because excess Glu in synapses leads to neuronal apoptosis . Memantine, at the time of this review, is the only NMDA antagonist available on the market. Memantine has been shown to be neuroprotective as well as increase LTP in CA1 hippocampal neurons [94–96]. Both NMDA antagonists and AChEI’s have been shown to have neurotrophic effects [97,98].
Lithium carbonate (Li2CO3)
Lithium Carbonate (Li2CO3) is an FDA approved agent used to treat Bipolar disorder and other behavioral disorders. Research has shown that Lithium Carbonate can inhibit GSK-3β and GSK-3β is known to increase tau neurofibrils via tau phosphorylation [178,179].
In addition, an increase in GSK-3 was implicated in Aβ-induced neurodegeneration . Additionally, Li2CO3 protects newly proliferated neurons and other hippocampal neurons and increases neural precursors, but it is unknown if the compound is neurogenic or if it simply increases fetal progenitors [181–183].
However, Lithium Carbonate can cause serious side effects in AD patients and a 2017 study proposed that ionic co-crystal of Lithium Salicylate and 1-Proline (LISPRO) is a more effective form of Lithium (Li) treatment for Alzheimer’s because it creates higher and more stable levels of Li, is safer for patients and significantly reduced Aβ and tau-phosphorylation . More research about this alternate form of Li is needed.
Furthermore, Li is also of interest to the APP 5’ UTR translation model. It is an alkali metal that may impart anti-amyloid therapy by competing with iron to bind to the IRE RNA stem loop in APP mRNA. Therefore, it is critical to test the anti-amyloid efficacy of lithium via the IRP/APP IRE interaction in the 5’ UTR of APP transcript while noting that Li, at the same time, may enhance neurogenesis.
More information: Edward N. Wilson et al, NP03, a Microdose Lithium Formulation, Blunts Early Amyloid Post-Plaque Neuropathology in McGill-R-Thy1-APP Alzheimer-Like Transgenic Rats, Journal of Alzheimer’s Disease (2019). DOI: 10.3233/JAD-190862