Lithium: A Missing Mineral That Could be Worsening Alzheimer's

Abnormal  protein deposits known as 1^✔).

Earlier work has pointed toward a possible role of metal balance in the brain, although how metals influence disease progression has not been clearly explained.

A team led by Dr. Bruce Yankner at Harvard Medical School investigated how metal ions, which are electrically charged metal atoms, could affect brain activity and contribute to Alzheimer's disease.

The group began by examining whether metal levels in the brain differ among individuals with mild cognitive impairment, Alzheimer's disease, or no cognitive impairment. Mild cognitive impairment occurs before Alzheimer's disease and involves greater difficulty with thinking, memory, and reasoning than is expected with normal aging.

Metal Imbalance in Early Cognitive Decline

To answer this question, the scientists studied post-mortem brain tissue and measured 27 different metals in specific brain regions. Samples from dozens of individuals with Alzheimer's disease were compared with those from people with mild cognitive impairment and those without cognitive decline. These findings were published in the journal Nature.

The analysis revealed a marked reduction in naturally occurring lithium levels in the prefrontal cortex of individuals with mild cognitive impairment and Alzheimer's disease.

This brain region is essential for memory and decision-making and is heavily affected in Alzheimer's disease. None of the remaining metals showed significant changes in individuals with mild cognitive impairment.

Lithium Sequestration Inside Amyloid Plaques

Because earlier evidence suggested that metal ions may interact with amyloid plaques, the researchers compared lithium levels in plaque-rich areas with regions free of plaques in human brain samples.

Lithium was found in high concentrations within amyloid plaques, and plaque-associated lithium increased as the disease progressed from mild cognitive impairment to Alzheimer's disease.

At the same time, lithium levels in plaque-free brain regions were significantly lower in Alzheimer's disease samples, indicating that lithium becomes trapped inside amyloid plaques.

Lithium Depletion Triggers Memory Loss and Brain Damage

The team then investigated how lithium depletion influenced Alzheimer's disease development using mouse models. When Alzheimer's disease mice were given a diet low in lithium, they developed significantly more amyloid plaques and tau tangles and showed impaired learning and long-term memory.

Older mice without Alzheimer's disease pathology that consumed a lithium-deficient diet displayed increased levels of amyloid protein and experienced notable memory loss. Lithium depletion also altered gene activity across major brain cell types.

Lithium Replacement and Disease Reversal

Next, the researchers examined whether restoring lithium could alter Alzheimer's disease pathology. Lithium carbonate, a drug commonly prescribed as a mood stabilizer for bipolar disorder, was evaluated first. However, it showed a strong attraction to negatively charged amyloid plaques, limiting its effectiveness.

After testing different lithium salts, the team identified lithium orotate, an organic lithium compound, as a promising alternative. Both lithium carbonate and lithium orotate were administered at low doses in drinking water to mouse models of Alzheimer's disease.

Lithium carbonate produced minimal benefits. In contrast, lithium orotate significantly reduced amyloid plaque accumulation and tau tangle formation. It also restored synaptic connections and reversed memory impairment in Alzheimer's disease mice, effects that were not seen with lithium carbonate.

Protective Effects in Normal Brain Aging

The final phase explored whether dietary lithium could protect the aging brain. Low-dose lithium orotate prevented synapse loss and reversed cognitive decline in aging mice without Alzheimer's disease pathology. Importantly, long-term administration of lithium orotate did not result in toxicity.

Dr. Yankner noted that the possibility of lithium deficiency contributing to Alzheimer's disease introduces a new perspective on treatment strategies. He emphasized that determining safe and effective dosage levels in people is essential before recommendations can be made and confirmed that plans are underway to begin a clinical trial of lithium orotate in the near future.

In conclusion, growing evidence shows that lithium deficiency in the brain may contribute directly to Alzheimer's disease by promoting amyloid plaque buildup, synapse loss, and memory decline. The ability of lithium orotate to reverse these changes in aging and disease models highlights a potential new approach to protecting cognitive health and slowing neurodegeneration.

Reference:

1. Lithium levels tied to Alzheimer’s disease and dementia - (https://www.nih.gov/news-events/nih-research-matters/lithium-levels-tied-alzheimers-disease-dementia)

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