September 9, 2025
At a Glance
- Levels of lithium were significantly reduced in the prefrontal cortex of people with mild cognitive impairment and Alzheimer’s disease (AD).
- In a mouse model of AD, a low-dose lithium salt in the diet reversed memory loss and prevented cognitive decline in aging mice.
- While more study is needed, lithium replacement could be a potential approach to prevent and treat AD.
Compared to mice with normal levels of lithium in the brain (left column), mouse models of Alzheimer’s disease have increased levels of amyloid beta deposits (top right) and tangled tau protein (bottom right).
Yankner Lab
The brains of people with AD have abnormal protein deposits called amyloid plaques and tau tangles. Despite much progress in understanding AD, there is still uncertainty about how the disease develops. Previous research has found that the balance of metals in the brain may play a role, but the nature of this role has been unclear.
A research team led by Dr. Bruce Yankner at Harvard Medical School set out to explore how metal ions—charged atoms of metals—might affect brain function and AD. The researchers first looked at whether metals in the brain differed in those who have mild cognitive impairment (MCI) or AD. In MCI, which precedes AD, people have more difficulty thinking, remembering, and reasoning than normal for people their age.
The scientists analyzed post-mortem brain samples to quantify 27 metals in certain parts of the brain. They compared levels from dozens of people with AD, with MCI, and with no cognitive impairment. The results were published in Nature on August 6, 2025.
The team found significantly lower levels of naturally occurring lithium in the prefrontal cortex of people with MCI and AD. The prefrontal cortex, which controls memory and decision-making, is prominently affected in AD. None of the other metals were significantly altered in people with MCI.
Prior studies suggested that metal ions may interact with amyloid plaques. So the researchers compared lithium in plaques with plaque-free regions in human brain samples. They found that lithium was highly concentrated in amyloid plaques, and that the amount of lithium in the plaques increased from MCI to AD. Lithium levels in plaque-free regions were also significantly reduced in AD samples. These results suggest that lithium is sequestered by amyloid plaques.
The researchers next explored how lithium in the brain affected AD pathogenesis in mouse models by depleting it from the diet. AD mice fed a reduced lithium diet had significantly more amyloid plaque and tau tangles along with impaired learning and long-term memory. In aged mice without AD pathology, those fed a low-lithium diet showed increased levels of the plaque-forming amyloid protein and developed significant memory loss. Lithium depletion affected gene activity in major brain cell types.
Next, the researchers tested whether replacing lithium might influence AD pathology. Lithium carbonate is used as a mood stabilizer to treat bipolar disorder. But the researchers found that it is highly attracted to negatively charged amyloid plaques. The team tested 16 different lithium salts to find an alternative and settled on the organic salt lithium orotate.
The researchers tested lithium carbonate and lithium orotate in AD mouse models at low doses in drinking water. Treatment with lithium carbonate had little effect. But lithium orotate significantly reduced amyloid plaque burden and tau tangle accumulation. Lithium orotate also restored synapses and reversed memory loss in AD mice, yet lithium carbonate did not.
Finally, the team evaluated whether dietary lithium could have a protective effect in normal brain aging. They found that low-dose lithium orotate prevented synapse loss and reversed cognitive decline in aging mice. Long-term treatment with lithium orotate did not show toxicity.
“The idea that lithium deficiency could be a cause of Alzheimer’s disease is new and suggests a different therapeutic approach,” Yankner says. But, he cautions, “Before recommending lithium orotate, we need to determine the effective and safe dose range in people. We are planning a clinical trial of lithium orotate that will hopefully begin in the near future.”
—by Karen Olsen, Ph.D.
Related Links
References
Lithium deficiency and the onset of Alzheimer’s disease. Aron L, Ngian ZK, Qiu C, Choi J, Liang M, Drake DM, Hamplova SE, Lacey EK, Roche P, Yuan M, Hazaveh SS, Lee EA, Bennett DA, Yankner B. Nature 2025 Aug 6. doi: 10.1038/s41586-025-09335-x. Online ahead of print. PMID: 40770094.
Funding
NIH’s National Institute on Aging (NIA); Ludwig Family Foundation; Glenn Foundation for Medical Research; Aging Mind Foundation.