Lithium and Alzheimer's Disease: What Does the Research Actually Show?

When most people hear the word lithium, they probably think of a medication used to treat bipolar disorder. But lithium is also a naturally occurring element found in our environment—and in very small amounts in the human body. Recently, researchers have been asking a very different question about lithium: could it play a role in protecting the brain?

The emerging science isn't about using psychiatric doses to treat dementia. Rather, it centers on a much quieter question of brain biology: Does physiological lithium play a protective role in the brain, and what happens when neurodegenerative disease disrupts it?

A paper led by Dr. Bruce Yankner's laboratory at Harvard Medical School, published in Nature, has sparked genuine interest across the medical community.¹ But understanding what this work means—and what it doesn't—requires looking closely at the crucial distinction between observational human findings, animal models, and human clinical evidence.

The Trace Mineral Clue

For years, epidemiological studies have explored whether naturally occurring lithium exposure in municipal drinking water is associated with dementia risk.² Several population studies have found intriguing associations between naturally occurring lithium in drinking water and dementia risk, although the findings have varied across populations.^2–4

However, the findings across drinking-water studies haven't been entirely consistent. Water contains hundreds of trace elements and environmental variables, and population-level correlation is not causation. To find out whether lithium might actually be involved in the disease process, researchers needed to look directly inside the human brain.

What They Found in Human Tissue

Yankner's team looked at lithium and other trace elements in brain tissue from people who had been cognitively healthy, had amnestic mild cognitive impairment (aMCI), or had Alzheimer's disease.¹

Of all the metals measured, lithium stood out as uniquely altered.

Researchers found that lithium levels were lower in an area of the brain affected by Alzheimer's disease in people with MCI, and even lower in people with Alzheimer's.¹ Interestingly, they didn't see the same change in an area of the brain that is typically less affected by the disease, or in the blood.

That matters because it suggests something may be happening specifically within the brain—not simply that people with Alzheimer's have less lithium throughout their bodies.

The Amyloid Connection

Why would lithium vanish from the specific brain tissue where it is needed most?

The researchers found a possible explanation for where the lithium was going: it appeared to be getting trapped in amyloid plaques.¹ As amyloid builds up, some of the lithium gets pulled into those plaques, leaving less available to the surrounding brain tissue.

What was especially interesting was that this change didn't seem to affect just one part of the disease. The researchers also found changes involving APOE, inflammation, and microglia—the immune cells of the brain—that looked similar to changes seen in Alzheimer's disease.¹

That raised another important question: Could having less lithium available in the brain actually make Alzheimer's-related changes worse?

Testing the Hypothesis in Mice

You cannot experimentally deplete trace elements in human brains to observe the damage, so researchers turned to animal models.

When they artificially reduced naturally occurring brain lithium in mice by roughly 50%, the consequences were remarkably broad across key hallmarks of neurodegeneration. The mice developed more amyloid and abnormal tau, more inflammation, loss of synapses and myelin, and worsening memory.¹

It is worth pausing right here.

This does not mean researchers have proven that lithium deficiency causes Alzheimer's disease in humans.

What they did was connect several important pieces:

• They found lower lithium levels in affected human brain tissue.
• They found that lithium appeared to get trapped in amyloid plaques.
• They showed in mice that lowering lithium could make several Alzheimer's-related changes worse.

That is much more compelling than an observational study alone, but a mouse model is still not a human clinical trial.

Restoring Tissue Levels: Comparing Formulations

When the researchers compared different lithium compounds to address this deficit, they found that standard lithium carbonate showed greater amyloid binding, while lithium orotate showed substantially less, allowing it to bypass the "amyloid sponge".¹

When low-dose lithium orotate was administered to mouse models, the downstream pathology changed significantly:

• Amyloid and tau pathology were reduced.¹
• Synaptic loss was reversed, and neuroinflammatory markers decreased.¹
• Memory performance improved in diseased mouse models.¹
• Healthy, aging mice were protected against age-related cognitive decline.¹

Equally important was the dose itself. The goal was not to reproduce the lithium exposures used in psychiatric treatment, but simply to restore the physiological lithium availability disrupted by the disease process, using concentrations roughly one-thousandth of conventional psychiatric doses.¹

Should You Start Taking Over-the-Counter Lithium Orotate?

No.

Because lithium orotate is widely available over the counter as a dietary supplement, the temptation for self-medication is high. However, taking over-the-counter supplements based on preliminary animal models carries real clinical risks:

Dr. Yankner himself explicitly cautioned against self-medicating based on these findings.⁵ Medical authorities, including reviews by Harvard Health, have reached the same grounded conclusion: we do not currently have solid clinical evidence proving that adjusting lithium levels prevents or treats Alzheimer's disease in people.⁶

What Do We Know From Human Studies?

This isn't the first time lithium has been studied in people with cognitive impairment. Earlier small studies looked at low-dose lithium carbonate in people with MCI and found some differences in cognitive performance and Alzheimer's-related biomarkers that suggested lithium was worth studying further.^7,8

More recently, the 2026 LATTICE pilot trial evaluated low-dose lithium carbonate in older adults with MCI.⁹ None of the study's six coprimary outcomes met its prespecified significance threshold, although verbal memory declined more slowly in the lithium group than in the placebo group. Importantly, the study enrolled people based on a clinical diagnosis of MCI rather than biomarker-confirmed Alzheimer's disease, and most participants who underwent amyloid testing were amyloid-negative.⁹ These findings were encouraging enough to justify further study, but they do not establish lithium as an effective treatment for MCI or Alzheimer's disease.

However, testing the specific lithium orotate / amyloid-bypass hypothesis requires a purpose-built trial design.

Now, researchers are getting ready to test lithium orotate in people. The LiO-AD trial (NCT07459959), led by Johns Hopkins University in collaboration with the National Institutes of Health, will study lithium orotate in adults with biomarker-confirmed early Alzheimer's disease.¹⁰ The Phase 1/2 study is expected to begin in October 2026.¹⁰

The study will last nine weeks and will test daily lithium orotate at increasing doses, from 240 mg up to 720 mg per day, providing up to 30 mg of elemental lithium.¹⁰ At this stage, researchers aren't trying to determine whether lithium orotate can slow or treat Alzheimer's disease. First, they need to answer some more basic questions:

• Is low-dose lithium orotate safe and well tolerated?
• Does it increase lithium levels in the cerebrospinal fluid, showing that the lithium is actually reaching the central nervous system?
• Does it change any of the Alzheimer's-related biomarkers researchers are measuring?

The Broader Picture: Science, Hope, and Evidence

There is a lot to be excited about here, and I think this research is genuinely interesting. But we also have to be careful not to get ahead of the science. Results in mice don't always translate to people, and we still don't know whether restoring lithium levels will have any meaningful effect on Alzheimer's disease in humans.

The Nature study gives us a new way to think about lithium and Alzheimer's disease. It suggests that as amyloid builds up, it may trap naturally occurring lithium and leave less available to the surrounding brain tissue. Whether replacing that lithium can make a meaningful difference in people with Alzheimer's disease is still unknown. But with human trials now being planned, we may finally be able to start answering that question.

References

1. Aron L, Ngian ZK, Qiu C, et al. Lithium deficiency and the onset of Alzheimer's disease. Nature. 2025;645(8081):712-721. doi:10.1038/s41586-025-09335-x
2. Kessing LV, Gerds TA, Knudsen NN, et al. Association of lithium in drinking water with the incidence of dementia. JAMA Psychiatry. 2017;74(10):1005-1010. doi:10.1001/jamapsychiatry.2017.2362
3. Fajardo VA, Fajardo VA, LeBlanc PJ, MacPherson REK. Examining the relationship between trace lithium in drinking water and the rising rates of age-adjusted Alzheimer's disease mortality in Texas. J Alzheimers Dis. 2018;61(1):425-434. doi:10.3233/JAD-170744
4. Muronaga M, Terao T, Kohno K, Hirakawa H, Izumi T, Etoh M. Lithium in drinking water and Alzheimer's dementia: epidemiological findings from National Data Base of Japan. Bipolar Disord. 2022;24(8):788-794. doi:10.1111/bdi.13257
5. Dutchen S. Could lithium explain—and treat—Alzheimer's disease? Harvard Medical School. Published August 6, 2025. Accessed August 16, 2026. https://hms.harvard.edu/news/could-lithium-explain-treat-alzheimers-disease
6. Will lithium supplements be used to fight Alzheimer's one day? Harvard Health Publishing. Published February 19, 2026. Accessed August 16, 2026. https://www.health.harvard.edu/brain-health/will-lithium-supplements-be-used-to-fight-alzheimers-one-day
7. Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz WF. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry. 2011;198(5):351-356. doi:10.1192/bjp.bp.110.080044
8. Forlenza OV, Radanovic M, Talib LL, Gattaz WF. Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial. Br J Psychiatry. 2019;215(5):668-674. doi:10.1192/bjp.2019.76
9. Gildengers AG, Ibrahim TS, Anderson SJ, et al. Low-dose lithium for mild cognitive impairment: a pilot randomized clinical trial. JAMA Neurol. 2026;83(4):310-319. doi:10.1001/jamaneurol.2026.0072
10. Johns Hopkins University. LiO-AD: lithium orotate in Alzheimer's disease feasibility, biomarker engagement, and clinical response (LiO-AD). ClinicalTrials.gov identifier: NCT07459959. Updated June 8, 2026. Accessed August 16, 2026.