02. Lithium Orotate: Breakthrough Treatment for Alzheimer’s Disease?

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Of all the studies we have covered, this one might be the most impactful. You will want to pay attention. It may shift how we think about prevention in Alzheimer’s disease.

A little over a year ago, we discussed the FDA’s approval of donanemab, an intravenous monoclonal antibody treatment for Alzheimer’s that along with several other similar medications represented a major breakthrough in the field. These treatments slow cognitive decline in a more meaningful way than had been seen previously with oral medications. One year later, lecanemab and donanemab are now gold standard treatments for Alzheimer’s disease offered via weekly or monthly infusions at many major medical centers.

While that’s really great news for patients and families. But we still haven’t discovered a medication that is capable of reversing the cognitive decline or better yet preventing it in the first place for patients who may be at risk. That would really be the holy grail of Alzheimer’s treatment.

We aren’t there yet but a new study raises the question of whether the holy grail has been hiding right under our noses this whole time. That would be of course an apt metaphor for Alzheimer’s disease where anosmia often precedes cognitive decline by months to years. A new study published in Nature earlier this year offers some hope for a eureka moment.

Lithium Depletion Found in Early MCI

The study led by Bruce Yankner at Harvard analyzed 27 metals to see if any were depleted in the brains of individuals with mild cognitive impairment and Alzheimer’s. Interestingly, they found that lithium was already low in patients with mild cognitive impairment. Lithium was further depleted by sequestration in amyloid plaques once patients began forming them.

Next, they removed lithium from the diet of mice including those with a mouse model of Alzheimer’s. Reduction of lithium in the diet by 50% led to the formation of beta-amyloid and tau plaques as well as to microglial activation and accelerated cognitive decline.

Finally, the authors supplemented the mouse diet with lithium orotate. They found that it prevented the pathological changes and cognitive decline in both normal mice and those with the mouse model of Alzheimer’s. Amazingly, supplementation with lithium orotate actually restored synapses and reversed memory loss in the Alzheimer’s mice.

Unified Hypothesis of Alzheimer’s Pathology

The authors hypothesized that sequestration of lithium by amyloid plaques depletes lithium levels in specific brain regions such as the prefrontal cortex. Lower lithium levels then impair microglial clearance of plaques which in turn leads to greater lithium sequestration.

Simultaneously, lithium depletion may lead to increased tau accumulation which causes inflammation leading to the loss of synapses, axons and myelin. This theory is notable because it presents a unifying hypothesis of the various changes that take place in the brains of patients with Alzheimer’s.

Lithium Orotate Explained

So what is lithium orotate? Well, importantly, it’s different from other forms of lithium that we typically use in Psychiatry to treat, for example, bipolar disorder which include lithium carbonate and lithium citrate. Those forms of lithium actually do tend to be sequestered by amyloid plaques.

This could explain why the commonly used forms of lithium haven’t been observed to prevent or reverse cognitive decline in patients with mood disorders. But lithium orotate is unique in the fact that it is not attracted to the negatively charged amyloid plaques allowing it to avoid sequestration.

Cautious Optimism: Lower Doses Without Typical Toxicity

Scientists are optimistic that lithium orotate may also avoid the long-term side effects that plague chronic lithium use especially in older patients which include kidney and thyroid disease. In the mouse models in this study, there were no toxic effects observed.

It’s also worth noting that the doses used were dramatically lower than doses we would think about for mood disorders. Instead of 300 to 1200 mg, the typical supplementation dose for lithium orotate is 5 mg though it’s unclear whether this dose will be sufficient in humans. Lithium orotate is already available as an over-the-counter supplement at drugstores and online.

Should We Be Recommending Lithium Orotate ?

A big question that I’ve heard since the study was published is whether we should be recommending lithium orotate for our patients with Alzheimer’s or those at risk or even taking it ourselves. While some psychiatrists and neurologists have started advocating for this, in every interview he has done, Dr. Yankner has made it clear that he doesn’t recommend this yet.

There is still too much unknown about the long-term effects of lithium orotate in humans. He also points out that the supplement industry is so poorly regulated that you often don’t know what you’re actually taking. His research group is planning to launch a clinical trial in patients soon but until then the recommendation is to not start recommending it for our patients.

I have to imagine though that for patients and families already living with the illness there will be some who view the potential benefits as significantly outweighing the risks and may start supplementing on their own. So it’s probably worth talking to patients about and asking them about.

Natural Dietary Sources Contain Lithium

In the meantime, lithium is found naturally in several foods. These include:

• Nuts
• Leafy greens
• Cereal
• Lentils (which actually have the highest lithium content of any food)

I found this interesting because it has been observed for some time now that sticking to a diet similar to that eaten in certain parts of India may reduce the risk for Alzheimer’s. Perhaps this observation also has something to do with intake of high lithium-content foods like lentils.

Important Caveats and Future Directions

There are of course lots of caveats here, the biggest one being that mice are not people. Lots of therapies have shown great promise in mouse models only to have disappointing results in humans so we certainly shouldn’t jump to any premature conclusions. Lots more data is needed before lithium orotate is ready for primetime.

However, if the clinical trials turn out to be successful, this is the kind of finding that would be Nobel Prize worthy. It builds on the work of many others going back at least 20 years showing potential benefit for lithium therapy in cognitive decline in mouse models and even some reduced risk of Alzheimer’s among individuals drinking lithium-enhanced water. But this latest study is really a potential game changer. It’s certainly the most exciting paper I’ve read this year.

Abstract

Lithium deficiency and the onset of Alzheimer’s disease

The earliest molecular changes in Alzheimer’s disease (AD) are poorly understood1,2,3,4,5. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, Li was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to AD. Li bioavailability was further reduced in AD by amyloid sequestration. We explored the role of endogenous Li in the brain by depleting it from the diet of wild-type and AD mouse models. Reducing endogenous cortical Li by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice. These findings reveal physiological effects of endogenous Li in the brain and indicate that disruption of Li homeostasis may be an early event in the pathogenesis of AD. Li replacement with amyloid-evading salts is a potential approach to the prevention and treatment of AD.

Reference

Aron, L., Ngian, Z.K., Qiu, C. et al. Lithium deficiency and the onset of Alzheimer’s disease. Nature 645, 712–721 (2025). https://doi.org/10.1038/s41586-025-09335-x