A study published in Nature by researchers at Harvard Medical School reports that lithium depletion in the brain appears to be an early driver of Alzheimer’s disease. In post-mortem tissue from 285 donors, lithium was the only one of 27 metals that fell significantly with disease severity, averaging 36 percent lower in the prefrontal cortex of people with Alzheimer’s and 23 percent lower in those with mild cognitive impairment. The team also found that amyloid plaques, a hallmark of the disorder, sequestered almost three times as much lithium as plaque-free regions, further reducing the metal’s availability to neurons. To test causality, the scientists fed genetically engineered Alzheimer’s-model mice a diet lacking 92 percent of normal lithium. After eight months, the animals accumulated about 2.5 times more amyloid deposits, showed increased tau tangles and inflammation, and took roughly 10 seconds longer to locate a hidden platform in water-maze memory tests than control mice. Conversely, supplementing ageing or diseased mice with trace amounts of lithium orotate—a form less readily trapped by amyloid than conventional lithium carbonate—reduced plaque burden by about 70 percent over nine months and restored performance on memory tasks to levels seen in healthy mice. The dosage was around 1,000-fold lower than that used to treat bipolar disorder and produced no signs of kidney or thyroid toxicity during the study period. The findings point to lithium depletion as a potential upstream mechanism in Alzheimer’s pathology and suggest that physiological replacement could offer a multi-target therapy, simultaneously addressing amyloid accumulation, tau phosphorylation and neuroinflammation. The authors caution that the results, while encouraging, are preclinical and that human trials will be needed to determine whether low-dose lithium orotate can safely slow or reverse cognitive decline.