5-Min Science: Lithium Deficiency May Be an Early Alzheimer's Driver

Abstract

A groundbreaking new study by Aron and colleagues (2025) has uncovered something surprising about Alzheimer's disease: the brain needs tiny amounts of lithium to stay healthy, and people with Alzheimer's don't have enough of it.

The researchers discovered that people with mild cognitive impairment (early memory problems) and Alzheimer's disease have much lower levels of natural lithium in their brains compared to healthy people. This isn't just a coincidence.

By studying both human brain tissue and specially bred mice that develop Alzheimer's symptoms, the scientists showed that when the brain doesn't get enough lithium, all the major signs of Alzheimer's get worse. These include the buildup of harmful proteins called amyloid-beta, damage to another protein called tau, loss of connections between brain cells, damage to the protective coating around nerves, and memory problems.

Here's the exciting part: a special form of lithium called lithium orotate can reverse these problems when given in tiny, safe doses. Unlike regular lithium supplements, this form doesn't get stuck in the protein clumps that form in Alzheimer's brains.

What is the Science Regarding Lithium?

Lithium is the lightest metal on Earth, and while most people know it as a mood stabilizer for bipolar disorder, it does much more in our brains. Inside brain cells, lithium blocks an enzyme called GSK3β (glycogen synthase kinase-3 beta). When this enzyme is too active, it damages tau proteins and breaks down the connections between brain cells and the protective insulation around nerve fibers.

What makes this study special is that it looks at lithium at natural levels: the tiny amounts normally found in our bodies, not the much higher doses used as medication. The researchers show that these trace amounts are essential for healthy brain aging and protecting against Alzheimer's.

What Did They Study?

The research team measured lithium levels in a brain region called the prefrontal cortex, which handles complex thinking and decision-making. They compared samples from people with normal aging, those with mild cognitive impairment (MCI, often an early stage of Alzheimer's), and those with full Alzheimer's disease.

They also studied mice that were genetically modified to develop Alzheimer's symptoms (called 3xTg and J20 mice) and normal aging mice. Using advanced techniques including genetic analysis, protein studies, immune cell testing, and memory tests, they explored what happens when the brain doesn't get enough lithium.

Finally, they compared two types of lithium supplements: lithium carbonate (the common form) and lithium orotate, to see which one could better reach brain areas affected by Alzheimer's.

How Did They Do It?

The researchers used a technique called ICP-MS (inductively coupled plasma mass spectrometry), essentially a super-sensitive metal detector, to measure 27 different metals in brain tissue after death.

Lithium stood out as the only metal that was consistently low in the prefrontal cortex of people with MCI and Alzheimer's, though levels remained normal in the cerebellum, a brain region that controls movement.

Using another imaging technique that works like a microscopic metal scanner, they discovered why: lithium gets trapped in the amyloid plaques (protein clumps) that are a hallmark of Alzheimer's, making it unavailable to the rest of the brain tissue.

Gene activity analysis revealed that lithium-deficient mice showed patterns remarkably similar to early-stage human Alzheimer's.

Treatment with lithium orotate, but not lithium carbonate, successfully restored lithium levels in brain areas without plaques and reversed the damage.

What Did They Find?

The study revealed that lithium deficiency shows up early and consistently in both MCI and Alzheimer's, making it unique among metal imbalances in the brain. When mouse brains had just half the normal amount of lithium, the animals developed significantly more amyloid-beta and damaged tau proteins, showed early memory problems, had activated immune cells, and lost nerve insulation.

These problems happened because GSK3β became overactive and Wnt signaling was suppressed when lithium was missing. The brain's immune cells, called microglia, couldn't clear away amyloid properly when they lacked lithium, and they turned on genes linked to Alzheimer's risk, including Apoe and Trem2.

Most remarkably, lithium orotate improved memory and restored brain structure in both Alzheimer's model mice and normal aging mice, even reversing advanced disease signs, all without causing toxic side effects.

What Were the Strengths and Limitations?

This research stands out for its thorough approach, combining studies of human brain tissue with detailed experiments in mice. The fact that lithium loss was confirmed in multiple groups of human patients, backed up by behavioral and molecular data from mice, makes the findings particularly convincing. The discovery that lithium orotate can bypass the trap of amyloid plaques is genuinely novel.

However, the study hasn't yet tested long-term lithium orotate treatment in humans, and researchers haven't fully ruled out that the orotate part of the compound might have its own effects. The study also focused mainly on the hippocampus (memory center) and cortex (thinking areas) without fully examining lithium dynamics throughout the entire brain.

What Was the Impact?

This study fundamentally changes how we think about lithium: it's not just a psychiatric drug but a protective micronutrient that the brain needs to stay healthy, and this balance is disrupted early in Alzheimer's disease.

The research identifies lithium deficiency as something we can potentially fix through diet or supplements, suggesting that restoring normal lithium levels with a brain-friendly form like lithium orotate could prevent or even reverse Alzheimer's damage.

The potential impact on public health and early intervention strategies is enormous, especially since lithium orotate appears safe at low doses. If these findings translate to humans, we could be looking at a completely new approach to preventing Alzheimer's disease.

Five Takeaways

1. Lithium deficiency precedes Alzheimer’s pathology and may act as an early molecular event in cognitive decline.

   
   

2. Lithium supports multiple neuronal and glial functions, including tau regulation, myelination, synaptic maintenance, and anti-inflammatory signaling.

   
   

3. Amyloid plaques sequester lithium, reducing its availability in the brain and potentially fueling a feedback loop of degeneration.

   
   

4. Lithium orotate bypasses amyloid binding, restores lithium levels in critical brain regions, and reverses AD-like pathology in mouse models.

   
   

5. Physiological lithium restoration could be a safe, low-cost preventive strategy for delaying or halting Alzheimer’s progression.

Glossary

Aβ (Amyloid-beta): a peptide fragment derived from amyloid precursor protein that aggregates into plaques in Alzheimer’s disease and is toxic to neurons.

astrogliosis: a reactive process in which astrocytes proliferate and hypertrophy in response to brain injury or disease, often contributing to inflammation.

beta-catenin: a protein involved in Wnt signaling that promotes gene transcription for cell survival, growth, and myelination; its nuclear presence is suppressed in lithium deficiency.

cognitive impairment: a decline in memory, attention, or other thinking skills that is more severe than normal aging but does not necessarily meet criteria for dementia.

demyelination: the loss or damage of the myelin sheath surrounding axons, impairing signal conduction and contributing to neurodegeneration.

excitatory neurons: neurons that release neurotransmitters (e.g., glutamate) to stimulate activity in other neurons.

GSK3β (glycogen synthase kinase 3 beta): a kinase that phosphorylates tau and β-catenin; its overactivation promotes neurodegeneration and inflammation.

inductively coupled plasma mass spectrometry (ICP-MS): a sensitive analytical technique used to quantify trace metal concentrations in biological tissues.

lithium orotate: a lithium salt of orotic acid that delivers lithium at low doses. It exhibits lower ionization and reduced binding to amyloid compared to lithium carbonate, allowing better brain bioavailability in Alzheimer’s disease models.

microglia: the brain’s resident immune cells that survey the microenvironment and clear debris; they become reactive in disease states like AD.

mild cognitive impairment (MCI): a transitional stage between normal aging and dementia, often characterized by memory deficits without significant functional impairment.

myelination: the process by which oligodendrocytes wrap axons in myelin, a lipid-rich sheath that facilitates efficient electrical conduction.

neurodegeneration: the progressive loss of structure or function of neurons, including synapse loss, axonal degeneration, and cell death.

neurofibrillary tangles (NFTs): aggregates of hyperphosphorylated tau protein found in the brains of individuals with Alzheimer’s disease.

neuroinflammation: inflammatory responses within the brain, often driven by activated microglia and astrocytes, contributing to neuronal damage.

oligodendrocytes: glial cells responsible for forming and maintaining the myelin sheath in the central nervous system.

pathology: the structural and functional abnormalities characteristic of a disease process.

plaque (amyloid plaque): extracellular accumulations of amyloid-beta peptides, a hallmark of Alzheimer’s disease.

reactive microglia: a phenotype of microglia characterized by upregulation of inflammatory markers and reduced phagocytic capacity.

synapse: the junction between two neurons where communication occurs via neurotransmitter release and receptor binding.

synaptic plasticity: the ability of synapses to strengthen or weaken over time, which underlies learning and memory.

tau (protein): a microtubule-associated protein that stabilizes neuronal structure; abnormally phosphorylated tau forms intracellular tangles in Alzheimer’s disease.

Wnt signaling pathway: a developmental and neuroprotective pathway involving β-catenin, inhibited in Alzheimer’s pathology and lithium deficiency.

Reference

Aron, L., Ngian, Z. K., Qiu, C., Choi, J., Liang, M., Drake, D. M., Hamplova, S. E., Lacey, E. K., Roche, P., Yuan, M., Hazaveh, S. S., Lee, E. A., Bennett, D. A., & Yankner, B. A. (2025). Lithium deficiency and the onset of Alzheimer’s disease. Nature. https://doi.org/10.1038/s41586-025-09335-x

About the Author

Fred Shaffer earned his PhD in Psychology from Oklahoma State University. He earned BCIA certifications in Biofeedback and HRV Biofeedback. Fred is an Allen Fellow and Professor of Psychology at Truman State University, where has has taught for 50 years. He is a Biological Psychologist who consults and lectures in heart rate variability biofeedback, Physiological Psychology, and Psychopharmacology. Fred helped to edit Evidence-Based Practice in Biofeedback and Neurofeedback (3rd and 4th eds.) and helped to maintain BCIA's certification programs.

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