Alzheimer’s disease (AD) remains one of today’s most urgent health challenges, and scientists are still searching for ways to prevent it. One emerging area of interest for brain health focuses on trace elements, which are present in very small amounts in the body but are essential for biological function. Lithium, a naturally occurring trace element in the brain – and one that is also found in foods such as grains, vegetables, and legumes – plays a role in protecting specialized nerve cells that send signals in the brain known as neurons. In a new study, led by High-Risk, High-Reward Research (HRHR) NIH Director's New Innovator Award recipient Eunjung Alice Lee, Ph.D., of Boston Children’s Hospital, researchers discovered that lithium may also play a role in early molecular changes contributing to AD.  

Dr. Lee and her team at Boston Children’s Hospital, including Bruce Yankner, M.D., Ph.D., who previously received the NIH Director’s Transformative Research Award, found that a decline in lithium levels is one of the first detectable chemical changes linked to the buildup of amyloid and tau, proteins that accumulate abnormally in AD.

The research team measured 27 different metals in post-mortem human brain tissue from individuals who had no cognitive impairment, mild cognitive impairment (MCI) – a possible precursor to AD – and AD. Of the metals tested, lithium was the only one consistently and significantly lower in individuals with MCI and AD. In brains affected by AD, lithium was trapped in clusters of abnormal proteins called amyloid plaques, making it less available to protect neurons. This trapping worsened as the disease progressed.

To better understand lithium’s role, the researchers reduced dietary lithium in both healthy mice and mouse models of AD. Mice fed a low-lithium diet showed faster buildup of amyloid and tau, more inflammation, and signs of memory loss. When brain lithium levels dropped, the mice developed lesions typical of AD, overactive immune cells, and impaired communication between neurons. The researchers also found that low lithium levels in the brain switched on GSK3β, an enzyme known to drive amyloid and tau formation.

The researchers then tested lithium orotate, a compound that releases lithium slowly and binds less readily to amyloid plaques than standard lithium formulations. In AD-model mice, lithium orotate prevented amyloid and tau buildup, reduced inflammation, and preserved memory. The findings suggest that compounds like lithium orotate could offer a promising new way to prevent or slow AD. This approach points to a potential new class of therapies designed to restore the brain’s natural lithium balance and protect against early cognitive decline.

Since these results come from preclinical animal studies, more research and human clinical trials are needed to determine whether this strategy is safe and effective in people. If confirmed, safely delivering “amyloid-evading” forms of lithium could open an entirely new avenue for AD prevention and brain-health research. 

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, 645(8012), 712–721. https://doi.org/10.1038/s41586-025-09335-x