Lithium For Alzheimer Prevention: What Are We Waiting For
Why is there so little clamor for a drug that prevents neurodegeneration, carries very low risk, and is unlikely to produce significant side effects?
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RESEARCH UPDATE
Imagine a drug company working on a pill to prevent progression to Alzheimer dementia for patients at high risk. Imagine that their animal studies show benefit in preventing neurodegeneration, reducing 2 of the major changes known to lead to Alzheimer disease: tau protein phosphorylation and amyloid plaque formation. Imagine that their new drug had been shown to inhibit these 2 changes in humans, in a preliminary trial and that so far, there were no known risks of their new medication, and no side effects in over 90% of patients.
Wouldnt some patients and their families be interested in getting hold of this drug, even as formal clinical trials were getting underway?
That would surely be the case if the drug was already known to carry very low risk and unlikely to produce significant side effects. Because what else is there to do, when a patient and his or her family are facing likely decline into a progressive series of losses and stress-with no hope of reversing the process?
If more people knew of this Alzheimer research, hesitation might decrease substantially.
MORE ABOUT James Phelps, MD
When work is a pleasure, life is a joy! When work is a duty, life is slavery.
-Maxim Gorky
Study Design And Participants
We performed a retrospective cohort study using data from the electronic clinical records of Cambridgeshire and Peterborough NHS Foundation Trust , UK, deidentified to create the CPFT Research Database . CPFT provides community and mental health services to a population of approximately 0.86 million people , covering both urban and rural areas. The present study examined those referred at some point to secondary care MH services. The MH electronic record contains patient information recorded by clinicians during routine treatment, including structured data and unstructured data . Routine blood tests for lithium, where recorded in the clinical notes, provide a measure of concordance.
We examined data between January 1, 2005 and December 31, 2019. For the cohort of patients exposed to lithium , each patients origin time was defined as their earliest recorded exposure to lithium . For the unexposed cohort , the origin time was the latest of their CPFT registration date or January 1, 2005. Follow-up was until the patients final record, death, or the first record of dementia, whichever occurred first. Eligible patients were those aged 50 years at baseline and had at least 1 year of follow-up. We excluded patients with a preexisting diagnosis of MCI or dementia or those diagnosed < 1 year after their origin time.
Improvement In A Matter Of Days
I was shocked when the patient saw improvement within a matter of days, says Guttuso. Since then, he discovered that during the pandemic, researchers in Spain had published findings revealing that patients who were already taking lithium for bipolar disorder who became acutely infected and hospitalized with COVID-19 had better outcomes than those not taking lithium.
Those findings, and the reports from his own patients, were intriguing. And when other physicians heard of Guttusos success, they began referring their patients with long COVID to him. Eventually, he was treating 10 additional long COVID patients with low-dose lithium nine saw improvement from lithium. None experienced side effects.
I just kept hearing the same story: that within days they were noticing satisfactory benefit, says Guttuso. Some said their symptoms didnt come back even after they stopped taking lithium, while others needed to keep taking it.
Jennifer Stewart of East Amherst was one of them. She had had a mild COVID-19 infection in January 2022, marked by few symptoms aside from brain fog and intense fatigue, which didnt let up even months later.
Im a really energetic person, I never nap, and here I was taking naps in the middle of the day, she recalls. I even slept through a Bills game I was going to watch on TV. Thats how bad it was.
Within about two days, I realized Holy cow, I dont need to take a nap, she says. That strong need for a nap had disappeared.
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Lithium: The Unlikely Treatment
One mineral that has shown great promise in the treatment of Alzheimers disease is the mineral lithium, a nutrient with established benefits for the treatment of mental health disorders.
Lithium salts have been used for centuries as a popular health tonic. Over the course of history this simple mineral has been used to heal ailments as wide-ranging as asthma, gout and migraine. Lithium springs were once sought-after health destinations, visited by authors, political figures and celebrities.
Throughout the 19th and into the 20th century, lithium was used as a mineral supplement to fortify a variety of foods and beverages. The third edition of theMerck Index, published in 1907, listed 43 different medicinal preparations containing lithium the following year, the 1908Sears, Roebuck & Co Catalogueadvertised Schieffelins Effervescent Lithia Tablets for a variety of afflictions and in 1929, a soft drink inventor named Charles Leiper Grigg even created a new lithiated beverage he called BibLabel Lithiated Lemon-Lime Soda, now known as 7-Up. The beverage contained lithium citrate until 1950, and was originally known and marketed for its potential to cure hangovers after a night of drinking alcohol, and to lift mood.
Lithium has even been officially added to the World Health Organizations list of nutritionally essential trace elements alongside zinc, iodine and others .
This incredible mineral is now being considered for the treatment of cognitive decline.
Patients See Improvements In Matter Of Days
I was shocked when the patient saw improvement within a matter of days, says Guttuso. Since then, he discovered that during the pandemic, researchers in Spain had published findings revealing that patients who were already taking lithium for bipolar disorder who became acutely infected and hospitalized with COVID-19 had better outcomes than those not taking lithium.
Those findings, and the reports from his own patients, were intriguing. And when other physicians heard of Guttusos success, they began referring their patients with long COVID to him. Eventually, he was treating 10 additional long COVID patients with low-dose lithium nine saw improvement from lithium. None experienced side effects.
I just kept hearing the same story: that within days they were noticing satisfactory benefit, says Guttuso. Some said their symptoms didnt come back even after they stopped taking lithium, while others needed to keep taking it.
Jennifer Stewart of East Amherst was one of them. She had had a mild COVID-19 infection in January 2022, marked by few symptoms aside from brain fog and intense fatigue, which didnt let up even months later.
Im a really energetic person, I never nap, and here I was taking naps in the middle of the day, she recalls. I even slept through a Bills game I was going to watch on TV. Thats how bad it was.
Within about two days, I realized Holy cow, I dont need to take a nap, she says. That strong need for a nap had disappeared.
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Clinical Trial Being Funded As Ctsi Pilot Project
The clinical trial is being funded as a pilot project by UBs Clinical and Translational Science Institute. Anyone with long COVID symptoms is also invited to participate in UBs Long COVID registry.
Because long COVID is believed to stem from chronic inflammation and lithium has known anti-inflammatory actions, Guttuso decided to recommend that a patient try low-dose lithium for persistent long COVID symptoms.
Why Was This Study Done
- Dementia is the leading cause of death and disability in elderly Western populations.
- Preventative interventions that could delay dementia onset even modestly would provide a major public health impact.
- Lithium has been proposed as a potential treatment, but limited population-level research has been conducted to support the idea that lithium might delay the onset of dementia.
Read Also: Can A Psychologist Diagnose Dementia
Clinical Trial Aims To Find Out If Low
Adults experiencing long COVID may be interested in a new University at Buffalo clinical trial that is testing low-dose lithium as a potential treatment.
The randomized clinical trial is recruiting 50 adults ages 18 to 80 with long COVID to participate. For more information on the trial, call 716-829-5454.
The placebo-controlled trial is examining the effects of low-dose lithium therapy on long COVID symptoms. It is a double-blind trial, meaning neither the patient nor the physician knows if the patient has received lithium or an inactive placebo. After the 21-day double-blind study phase, all patients will have the opportunity to receive lithium without the chance for a placebo for an additional 14 days.
Thomas J. Guttuso Jr., professor of neurology in the Jacobs School of Medicine and Biomedical Sciences and a physician with UBMD Neurology, is the principal investigator.
The clinical trial is being funded as a pilot project by UBs Clinical and Translational Science Institute. Anyone with long COVID symptoms is also invited to participate in UBs long COVID registry.
Because long COVID is believed to stem from chronic inflammation and lithium has known anti-inflammatory actions, Guttuso decided to recommend that a patient try low-dose lithium for persistent long COVID symptoms.
Dual Vaccine Shows Promise For Treating Alzheimers In Early Study
These findings will now inform the design of a Phase 2 trial to test multiple ascending doses in Alzheimers patients.
We look forward to swiftly initiating a Phase 2 multiple ascending dose study involving Alzheimers patients in the second quarter of 2022, said Jackman.
As lithium has been marketed for more than 35 years for several medical disorders with an established safety profile, the regulatory and development timeline for AL001 will likely be reduced.
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Lower Rates Of Dementia
Doctors have long used high doses of lithium to treat bipolar disorder and depression.
Scientists noticed that bipolar patients receiving lithium had lower rates of cognitive decline than patients on other medications.1 That got them interested in whether lithium could be used to treat neurodegenerative disorders.
To test this observation, researchers compared the rates of Alzheimers disease in 66 elderly bipolar patients using chroniclithium therapy with 48 similar patients who were not prescribed this mineral.
In patients receiving lithium, just 5% had Alzheimers, compared with 33% in the non-lithium group.2
Two studies in Denmark confirmed similar results. Investigators surveyed the records of over 21,000 patients who had received lithium treatment and found that it was associated with a reduced rate of Alzheimers and other forms of dementia.3,4
And in 2018, researchers studying lithium levels in different regions of Texas discovered that rates of death from Alzheimers diseasewere higher in areas with low levels of lithium in the water.5
This finding indicates that high lithium drug doses may not be needed to confer neuroprotection.
Based on findings from a 2020 study of Alzheimers disease in rats, scientists from McGill University have suggested that microdoses of lithium could slow the progression of Alzheimers in its initial stages and even improve cognition.6
Positive Results Inspires Authoring Of Book
Guttusos interest in low-dose lithium therapy goes beyond long COVID. He is currently conducting a clinical trial on using the therapy for people with Parkinsons disease with pilot project funding from UBs CTSI.
Based on the promising results he has observed, as well as previously published research studies, Guttuso was inspired to write a book about lithium.
The book is scheduled to be published Jan. 31.
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Lithium Microdose Could Stop Alzheimers From Advancing
Some recent studies in rodents have suggested that lithium may help treat Alzheimers disease. A new study in rats adds to this evidence, showing that a microdose of the compound can halt the progression of this neurodegenerative condition, even in its later stages.
In 2017, Medical News Today reported on a study that proposed that the mood stabilizer lithium might help stave off dementia.
The study found that people exposed to drinking water with higher concentrations of lithium were 17% less likely to develop dementia than people whose water contained barely any lithium.
Since then, other epidemiological, preclinical, and clinical studies have suggested that a microdose of lithium can reduce the risk of Alzheimers by influencing key pathological mechanisms at play in the neurodegenerative condition.
One such study appeared in the journal Translational Psychiatry . The study found that concentrations of lithium hundreds of times lower than what doctors usually prescribe for psychiatric conditions such as bipolar disorder can help improve early signs of Alzheimers in rat models.
Dr. Claudio Cuello at the Department of Pharmacology and Therapeutics at McGill University in Quebec, Canada was the senior author of that study.
Now, Dr. Cuello and his research team have set out to examine whether or not microdoses of lithium would have the same beneficial effects at later stages of the condition.
Lithium Effective After Toxic Plaque Buildup
According to the study authors, NP03 rescues functional deficits in object recognition tests, reduces levels of soluble and insoluble cortical beta-amyloid, and reduces the number of plaques in the brains hippocampus.
In addition, they write, NP03 reduces markers of neuroinflammation and cellular oxidative stress. Together, these results indicate that microdose lithium NP03 is effective at later stages of amyloid pathology, after appearance of plaques.
While it is unlikely that any medication will revert the irreversible brain damage at the clinical stages of Alzheimers, 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. Claudio Cuello
He is hopeful that the teams findings will soon translate into clinical trials, either testing NP03 with other drug candidates or testing it in populations at high risk of Alzheimers or adults who already have preclinical Alzheimers.
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.
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Testing The Old Microdose In New Rats
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 Alzheimers-like transgenic rat, explains Dr. Cuello, speaking of his earlier research.
The researchers called the lithium microdose formulation NP03. In their previous study, they applied it to a transgenic Alzheimers model, wherein rats expressed human proteins that triggered characteristics of Alzheimers disease, such as toxic accumulation of amyloid plaques in the brain and cognitive problems.
These results were remarkably positive, and they stimulated us to continue working with this approach on a more advanced pathology, notes Dr. Cuello.
So, in the new study, the researchers administered the same dose to transgenic rats at the equivalent of late preclinical stages of Alzheimers disease in humans. At this post-plaque stage, the beta-amyloid had already accumulated to such an extent that it had started to affect cognition.
The rats took the lithium for 12 weeks, and the researchers assessed their remote working memory using the novel object recognition test. Dr. Cuello and colleagues also examined markers of neuroinflammation in the rodents brains, levels of oxidative stress, and levels of beta-amyloid.
The Benefits Of Lithium For Dementia Treatment
For the last few decades, research has been building that shows lithium may be a disease-modifying treatment and preventative agent for Alzheimers disease and dementia.
A new study on prescription lithium found that the risk for dementia and Alzheimers disease was almost cut in half with lithium treatment.
Alzheimers disease is a devastating illness with current estimates suggesting more than 6 million Americans struggle with the condition and rates of Alzheimers are projected to rise, suggesting that by 2060, almost 14 million Americans will be afflicted .
As it currently stands, an Alzheimers diagnosis is a death sentence, where individuals slowly lose their memory and ability to function. Caring for patients with Alzheimers is extraordinarily expensive and difficult, with the burden often falling to unpaid family members. This unpaid caregiving is currently valued at over 250 billion dollars and is expected to rise as case rates increase .
Further compounding the problem, current standard treatments do not slow the inexorable progression of the disease, only having a modest impact on symptoms. While research has long suggested that functional and integrative approaches may have benefits for prevention and treatment, they have been almost categorically ignored by the medical establishment.
Lithium is a good example.
Resources on Low-Dose, Nutritional Lithium
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Lithium As A Treatment For Alzheimers Disease: The Systems Pharmacology Perspective
Article type: Review Article
Collaborators: AFSHAR, Mohammad | AGUILAR, Lisi Flores | AKMAN-ANDERSON, Leyla | ARENAS, Joaquín | AVILA, Jesus | BABILONI, Claudio | BALDACCI, Filippo | BATRLA, Richard | BENDA, Norbert | BLACK, Keith L. | BOKDE, Arun L.W. | BONUCCELLI, Ubaldo | BROICH, Karl | CACCIOLA, Francesco | CARACI, Filippo | CASTRILLO, Juan | CAVEDO, Enrica | CERAVOLO, Roberto | CHIESA, Patrizia A. | CORVOL, Jean-Christophe | CUELLO, Augusto Claudio | CUMMINGS, Jeffrey L. | DEPYPERE, Herman | DUBOIS, Bruno | DUGGENTO, Andrea | EMANUELE, Enzo | ESCOTT-PRICE, Valentina | FEDEROFF, Howard | FERRETTI, Maria Teresa | FIANDACA, Massimo | FRANK, Richard A. | GARACI, Francesco | GEERTS, Hugo | GIORGI, Filippo S. | GOETZL, Edward J. | GRAZIANI, Manuela | HABERKAMP, Marion | HABERT, Marie-Odile | HAMPEL, Harald | HERHOLZ, Karl | HERNANDEZ, Felix | KAPOGIANNIS, Dimitrios | KARRAN, Eric | KIDDLE, Steven J. | KIM, Seung H. | KORONYO, Yosef | KORONYO-HAMAOUI, Maya | LANGEVIN, Todd | LEHÉRICY, Stéphane | LUCÍA, Alejandro | LISTA, Simone | LORENCEAU, Jean | MANGO, Dalila | MAPSTONE, Mark | NERI, Christian | NISTICÓ, Robert | OBRYANT, Sid E. | PALERMO, Giovanni | PERRY, George | RITCHIE, Craig | ROSSI, Simone | SAIDI, Amira | SANTARNECCHI, Emiliano | SCHNEIDER, Lon S. | SPORNS, Olaf | TOSCHI, Nicola | VERDOONER, Steven R. | VERGALLO, Andrea | VILLAIN, Nicolas | WELIKOVITCH, Lindsay A. | WOODCOCK, Janet | YOUNESI, Erfan
DOI: 10.3233/JAD-190197