A groundbreaking Harvard Medical School study has identified lithium deficiency as a potential driver of Alzheimer's disease, revealing that people with the condition have significantly lower levels of this trace metal in their brains. The research, published in Nature, demonstrates that low-dose lithium orotate treatment can reverse cognitive decline in mice, offering new hope for treating the devastating neurodegenerative disorder.
Lithium Depletion Linked to Cognitive Decline
Researchers led by Dr. Bruce Yankner analyzed levels of 27 metals in the brains of 285 people after death, including 94 diagnosed with Alzheimer's disease and 58 with mild cognitive impairment. The study revealed that lithium levels in the prefrontal cortex—a brain region crucial for memory and decision-making—were approximately 36% lower in people with Alzheimer's disease compared to those without cognitive decline. Those with mild cognitive impairment showed 23% lower lithium levels.
"We suspect that's due to a number of environmental factors: dietary intake, genetics and so forth," said Yankner, the study's senior author.
The research uncovered a dual mechanism behind lithium depletion. Beyond reduced uptake, the team discovered that amyloid plaques—protein clumps characteristic of Alzheimer's—contained nearly three times the amount of lithium as plaque-free brain regions. "Lithium becomes sequestered in these plaques," Yankner explained. "We have two things going on. There is impaired uptake of lithium [in the brain] very early on and then, as the disease progresses, the lithium that is in the brain is further diminished by being bound to amyloid."
Mouse Studies Demonstrate Therapeutic Potential
To test the causal relationship between lithium deficiency and cognitive decline, researchers genetically engineered 22 mice to develop Alzheimer's-like symptoms and reduced their lithium intake by 92%. After eight months, these animals performed significantly worse on memory tests compared to 16 mice on a standard diet. Lithium-deficient mice took approximately 10 seconds longer to find a hidden platform in water maze tests, even after six days of training, and their brains contained nearly two and a half times as many amyloid plaques.
Genetic analysis revealed increased activity in neurodegeneration-related genes, along with heightened brain inflammation and reduced ability of immune cells to clear amyloid plaques—changes mirroring those seen in human Alzheimer's patients.
Lithium Orotate Shows Promise as Treatment
The research team screened various lithium compounds and identified lithium orotate—a naturally occurring compound formed by combining lithium with orotic acid—as least likely to become trapped within amyloid plaques. Nine months of treatment with this compound significantly reduced plaques in mice with Alzheimer's-like symptoms, and the animals performed as well on memory tests as normal mice.
This finding addresses a critical limitation of current lithium treatments. While lithium compounds are already used to treat psychiatric conditions like bipolar disorder, the high doses required often cause kidney and thyroid toxicity in aging individuals. The concentrations used in this study were approximately 1,000-fold lower than typical psychiatric doses, with no indication of kidney or thyroid dysfunction in treated animals.
Clinical Translation Challenges
Despite the promising preclinical results, significant challenges remain for clinical translation. "The challenge is, how do you determine whether somebody needs lithium?" noted Dr. Rudolph Tanzi at Massachusetts General Hospital. "Because you wouldn't want to overload the body with lithium. That could lead to severe side effects."
The research builds on previous epidemiological studies showing associations between lithium exposure and reduced Alzheimer's risk. A 2022 study found that people prescribed lithium have almost half the risk of developing Alzheimer's compared to those who haven't been prescribed the medication.
However, Dr. Yankner emphasized that current research funding constraints could significantly impact progress. The Trump administration's freeze on research funding "will significantly limit our progress," he warned, highlighting potential obstacles to advancing this promising therapeutic avenue.
The study represents a significant step toward understanding Alzheimer's disease mechanisms and developing targeted treatments. Clinical trials will be essential to determine the safety and efficacy of low-dose lithium orotate in humans, potentially offering a new therapeutic approach for a disease that affects millions worldwide.
