A study published in Nature has discovered a previously neglected factor in the early onset of a deficiency of naturally produced lithium (Li) in the brain of Alzheimer’s disease (AD). A study conducted by researchers at Harvard Medical School and collaborators found that decreased Li availability can not only indicate the onset of cognitive loss but also contribute to the disease process directly.
Analysis of brain tissue of individuals with mild cognitive impairment (MCI), AD, and no cognitive impairment, the researchers found that Li levels in the prefrontal cortex, a brain region that is heavily affected by AD, were considerably decreased in those who have AD and MCI as compared to healthy individuals. This decline was not found in the cerebellum, which is mostly unaffected by AD. Importantly, this lithium decline was confined to the brain, as blood levels remained stable.
Further investigation revealed that amyloid plaques, which are a pathological feature of AD, actively absorb Li and trap it in insoluble deposits, decreasing its availability to the brain cells. This trapping mechanism contributes to disease progression, suggesting that lithium deficiency may act both as a consequence and a driver of amyloid pathology.
Researchers placed AD-model and normal mice on lithium-deficient diets to investigate the biological consequences. The mice developed faster accumulation of amyloid-β, higher tau phosphorylation (a sign of neurofibrillary tangles), myelin and synaptic loss, impaired memory and learning, and increased microglial inflammation in weeks. These changes were largely driven by hyperactivation of the enzyme GSK3β, which is known to exacerbate tau and amyloid pathologies.
Single-nucleus RNA sequencing revealed that lithium deficiency changed the activity of hundreds of genes in many brain cell types, like microglia, astrocytes, oligodendrocytes, and neurons. Many of these alterations are similar to those seen in human AD brain samples. Microglia, immune cells of the brain, were more in a pro-inflammatory state and lost most of their capacity to eliminate amyloid plaques. The researchers investigated whether specific types of lithium could prevent the accumulation of lithium by amyloid plaques. They compared conventional psychiatric drug lithium carbonate with lithium orotate, an organic salt with weaker binding to amyloid and decreased electrical conductivity.
Low dosage of lithium orotate at concentrations that match natural lithium levels in the brain restored the availability of lithium in plaque-free brain tissue in AD mouse models. This decreased the tau and amyloid pathology and maintained myelin and synapses, enhanced memory performance, and reduced microglial inflammation. Lithium carbonate with the same dosage did not produce these advantages because it was trapped in plaques.
Lithium orotate was effective as a treatment in older mice and as a preventive measure in younger mice. Long-term administration of lithium orotate showed no detectable thyroid or kidney toxicity, which is a concern with increased dosage of lithium therapy used in psychiatric care.
The advantages of lithium orotate went beyond AD models. Treatment stopped memory loss, dendritic spine loss, and normal age-related brain inflammation in ageing mice. Higher brain lithium levels were linked with improved memory test and increased expression of synaptic protein associated with cognitive resilience in human brain samples from older persons with no cognitive impairment.
This study suggests that lithium depletion in the brain can lead to an early onset of the development of AD, which initiates a damaging cycle. Amyloid plaques accumulate lithium and decrease its availability, which impairs the ability of microglia to clear amyloid, accelerates the tau buildup, and leads to neuroinflammation and loss of brain connectivity. This study opens up the possibility of new preventive and therapeutic methods with lithium orotate to restore the lithium levels in affected brain areas without high systemic exposure. This can slow or stop the AD’s pathology before the symptoms appear.
Future human clinical trials are necessary to determine whether lithium orotate may reproduce these advantages in humans and at what dosages. An individual’s diet, genetic risk factors, and environmental exposures can affect lithium metabolism in the brain, highlighting the need for personalized therapeutic approaches.
Reference: Aron L, Ngian ZK, Qiu C, et al. Lithium deficiency and the onset of Alzheimer’s disease. Nature. 2025. doi:10.1038/s41586-025-09335-x
