Lithium’s Benefits for the Aging Brain and Alzheimer’s Disease
by Eric Roehm, MD 08-15-25
For lithium’s effects on normal aging, please see the last section
Breakthrough Study
In August 2025, Nature published a landmark paper by Aron et al.¹ from a Harvard Medical School team led by Bruce A. Yankner, MD, PhD, with lead author Liviu Aron, PhD. The article is the first publication of at least 10 related studies conducted over a decade. It is the first medical research paper I have read in 40 years that has made me think, “This deserves a Nobel Prize.”
Lithium Levels in the Human Brain
The researchers found that lithium (Li) was the only one of 27 metals significantly reduced in the prefrontal cortex of people with Alzheimer’s disease and those with mild cognitive impairment, compared with individuals who had normal cognition.¹ They reached this conclusion by analyzing post-mortem brain tissue, blood samples, and health records from the Rush Alzheimer’s Disease Center in Chicago.
When they looked at amyloid plaques—abnormal protein deposits tied to Alzheimer’s¹ ²—they discovered that lithium was several-fold higher inside plaques than in the surrounding tissue. Mouse studies suggested the plaques were sequestering (trapping) lithium, leaving the nearby brain cortex with low levels of lithium. Lower lithium levels outside plaques in people correlated with worse memory and cognition scores—even in those who otherwise appeared to be aging normally.¹
Different Forms of Lithium
The team also compared different forms of lithium. They hypothesized that lithium compounds with low conductance (less ionization in water) would be less likely to get trapped in plaques. Lithium carbonate—the standard psychiatric medication for bipolar disorder—has a high conductance. Among the compounds tested, lithium orotate had the lowest conductance.1 (Lower conductance here means a greater fraction of lithium orotate remains bound together in water, rather than splitting into free ions.3,4)
Lithium orotate is sold over the counter, but it has not been tested in large randomized clinical trials that would define optimal dosing and side-effect profiles.⁵
Animal Studies: Lithium
In Alzheimer’s mouse models, lithium levels were high in plaques but low in the non-plaque mouse brain cortex.
When the researchers compared lithium carbonate with lithium orotate in transgenic Alzheimer’s mice, lithium carbonate led to lithium being preferentially deposited in plaques, leaving non-plaque regions depleted. Lithium orotate led to much less sequestering, and lithium levels in non-plaque brain areas stayed well maintained—similar to the levels seen in normal young adult mice.
Both compounds were delivered to mice in drinking water at a very low dose (4.3 µEq Li per liter). These low doses produced serum lithium levels within the physiological range naturally found in aging humans and mice. (Early experiments using higher doses of either compound showed no added benefit over the low dose, so the higher concentrations were dropped.)
In wild-type mice, lithium orotate slightly elevated serum and brain lithium levels upward but still within natural ranges. For contrast, clinical treatment with the much higher doses of lithium carbonate used in psychiatry raises serum levels to nearly 1,000 times the endogenous concentration.¹
Dietary Lithium Deficiency and the Benefits of Lithium Orotate in Mice
The team then cut dietary lithium by 92%. The baseline lab diet matched a typical grain-based mouse diet, including the same lithium content.¹ On that baseline diet, mouse serum and cerebral cortex lithium levels were comparable to those seen in aging humans.¹ (Lithium isn’t officially recognized as a micronutrient, though some researchers have proposed intake recommendations.⁶)
On the low-lithium diet, both Alzheimer’s-model and aging wild-type mice developed neurodegenerative changes—neuron loss, dendritic damage, and other harmful alterations. Low-dose lithium orotate supplementation prevented these changes; lithium carbonate did not.
Lithium deficiency suppressed many genes needed to maintain key brain cell types and upregulated pathways linked to neurodegeneration. Strikingly, these mouse gene changes substantially overlapped with changes in gene activity observed in humans with Alzheimer’s disease.
Lithium Orotate in Aged Alzheimer’s-Type Mice
In aged Alzheimer’s-type mice with advanced pathology, lithium orotate reduced amyloid plaques by ~70% and significantly lowered phospho-tau (a component of neurofibrillary tangles). Lithium carbonate again showed no benefit.
Lithium and the Prevention of Normal Brain Aging
A particularly important aspect of this research is what this means for normal aging.
Human Data on Normal Aging
In 47 postmortem cases from individuals without cognitive impairment—people who also had blood samples and cognitive testing available—higher brain lithium indices were associated with more protective neuroproteins, specifically complexin-1 and complexin-2. With a higher cortex-to-serum lithium ratio, these proteins were increased, which predicts a resistance to Alzheimer’s.
Higher cortical lithium also correlated with better cognitive test scores for working-memory scores and better Mini-Mental State Examination performance.¹
Mouse Data on Normal Aging
In wild-type (non-Alzheimer’s-model) mice, lithium orotate—but not lithium carbonate—prevented age-related inflammation, neurodegeneration, and memory decline.¹
Study Details Showing Dramatic Improvement in Normal Aging
One experiment gave wild-type mice a normal diet plus low-dose lithium orotate from 12 to 24 months of age. (For context: at 3 months, mice are adults; at 12–24 months, there is significant aging; and 26–30 months is the average lifespan for one common strain.7)
Study groups:
- adult — young adult mice at 3 months used as a reference group
- aged/LiO — aging mice given lithium orotate from 12–24 months
- aged/NaO — aging mice given sodium orotate as a control (which showed no effect)
- aged — aging mice with no lithium orotate supplementation
Results: Only lithium orotate prevented age-related deterioration in microglia (the brain’s protective immune cells) and astrocytes (the most abundant glial cells), across the hippocampus, cortex, and corpus callosum. Lithium orotate also reversed age-related increases in inflammatory cytokines IL-6 and IL-1β.
Lithium orotate prevented synapse loss, preserving dendritic spines in the hippocampus (a key memory structure) at levels comparable to young mice. In another experiment, lithium orotate restored microglia’s ability to clear amyloid-beta.
Most strikingly, age-related memory decline was largely prevented in the lithium orotate group. And after 12 months (at least a third of a mouse’s life) of supplementation, there were no adverse effects on mouse kidney or thyroid function.¹
Final Summary
The Aron et al. Nature study is groundbreaking.
-In humans, lower lithium levels were linked to Alzheimer’s and mild cognitive impairment, while higher lithium levels in normal aging were tied to protective proteins and better cognition.
-In mice, lithium deficiency caused neurodegeneration—an effect prevented by lithium orotate but not lithium carbonate.
-Lithium orotate profoundly influenced normal aging in mice: maintaining youthful brain lithium levels, reducing plaques and tau tangles, blunting inflammation, and preserving memory.
-If confirmed in humans, these findings point to lithium orotate as a potentially transformative intervention for both Alzheimer’s disease and healthy brain aging—work that may ultimately merit a Nobel Prize.
Limitations:
While these findings are very impressive, it is important to recognize that the strongest evidence so far comes from mouse models and postmortem analyses. Lithium orotate has not yet been tested in large, long-term randomized trials in humans. The results are promising but preliminary, and any translation to clinical recommendations will require rigorous testing to establish both safety and effectiveness. -This article is informational and not medical advice. -ER
References
- Aron L, Ngian Z, Qiu C, et al. Lithium deficiency and the onset of Alzheimer’s disease. Nature. 2025. doi:10.1038/s41586-025-09335-x
- Abner E, Kryscio R, Schmitt F, et al. Outcomes after diagnosis of mild cognitive impairment in a large autopsy series. Ann Neurol. 2017;81(4):549-559. doi:10.1002/ana.24903
- Ohno H. Physical properties of ionic liquids for electrochemical applications. In: Endres F, Abbott A, MacFarlane D, eds. Electrodeposition from Ionic Liquids. 2nd ed. Wiley-VCH; 2017. doi:10.1002/9783527682706.ch3
- Timberlake KC. Chemistry: An Introduction to General, Organic, and Biological Chemistry. 14th ed. Pearson; 2024.
- Pacholko A, Bekar L. Lithium orotate: A superior option for lithium therapy? Brain Behav.2021;11(8):e2262. doi:10.1002/brb3.2262
- Szklarska D, Rzymski P. Is lithium a micronutrient? Biol Trace Elem Res. 2019;189(1):18-27. doi:10.1007/s12011-018-1455-2
- University of Alabama at Birmingham. Methuselah’s bestiary: C57BL/6 mice average lifespan. Accessed September 8, 2025. https://www.uab.edu/shockcenter/resources/methuselah-bestiary/1-5-years
