New research finds natural brain lithium depletion precedes symptoms and may offer a safe therapeutic route for prevention and treatment.
The role of lithium in brain health has been largely relegated to psychiatry, where it has been used for decades to treat bipolar disorder; however, new research from Harvard Medical School and collaborators positions this unassuming element in a different light – as a potential player in the earliest stages of Alzheimer’s disease and a modifiable factor in cognitive aging.
A new lens on an old element
The study, published in Nature, examined levels of 27 metals in post-mortem brain tissue from individuals with no cognitive impairment, mild cognitive impairment (MCI) and Alzheimer’s disease. Lithium was the only metal significantly reduced in the prefrontal cortex in both MCI and Alzheimer’s, with levels in serum remaining unchanged. The authors report that lithium is sequestered by amyloid plaques, reducing its bioavailability, and that dietary depletion of lithium in mouse models accelerates amyloid and tau pathology, promotes neuroinflammation, and hastens cognitive decline [1].
Senior author Bruce Yankner, professor of genetics and neurology in the Blavatnik Institute at HMS, was the first to show the toxic effects of amyloid beta in the 1990s [2]. “The idea that lithium deficiency could be a cause of Alzheimer’s disease is new and suggests a different therapeutic approach,” he said [3].
Longevity.Technology: Lithium has long been the preserve of psychiatry – a stalwart in the treatment of bipolar disorder – but this new research shifts the conversation in a new direction, revealing that this simple element is dynamically regulated in the brain and that its depletion may be an early and underappreciated driver of Alzheimer’s pathology. More intriguing still, the findings suggest that endogenous lithium is not merely a bystander but an active contributor to cognitive resilience during normal aging; in other words, keeping lithium levels in the sweet spot could help maintain memory and neuronal integrity well beyond the narrow confines of disease prevention. The work also highlights a tantalizing public health link – populations with higher lithium in drinking water have lower dementia incidence – and yet, unlike its pharmacological cousin, low-dose lithium orotate appears to operate within the body’s natural range without incurring the kidney and thyroid liabilities that have long dampened enthusiasm for lithium-based interventions [1].
The implications are broad – if lithium is, as the evidence increasingly suggests, an essential micronutrient for brain health, then it may be time to think of it alongside magnesium or zinc, rather than as a blunt psychiatric sledgehammer; the fact that it is an element, and thus unpatentable, may temper Big Pharma’s ardor – after all, there’s little commercial mileage in selling the periodic table. This makes the onus heavier on public research bodies and philanthropic funders to underwrite the next steps: the development of reliable biomarkers to measure brain lithium status, and the careful testing of amyloid-evading, low-dose formulations in those at risk or in the earliest disease stages. If these trials succeed, lithium’s story may turn out to be not about mood stabilization at all, but about stabilizing something far more fundamental – the very architecture of the aging brain.
From depletion to replacement
In the study, lowering dietary lithium in mice by about half caused rapid increases in amyloid-β deposition, accumulation of hyperphosphorylated tau, and microglial activation. These effects appeared within five weeks and were seen both in Alzheimer’s models and in normally aging wild-type mice. Molecular analysis revealed changes in gene expression across multiple brain cell types, many of which mirrored those seen in human Alzheimer’s tissue.
“What impresses me the most about lithium is the widespread effect it has on the various manifestations of Alzheimer’s. I really have not seen anything quite like it all my years of working on this disease,” said Yankner [3].
Lithium’s biological influence appears to operate partly through inhibition of glycogen synthase kinase 3β (GSK3β), a kinase implicated in tau phosphorylation and amyloid production. The authors found that lithium deficiency increased GSK3β activity, while pharmacological inhibition of GSK3β reversed many pathological changes, including synapse loss and impaired amyloid clearance by microglia [1].
Given that lithium becomes bound to amyloid deposits in the brain, the team sought a form less prone to sequestration. Lithium orotate, an organic salt with lower ionization in solution, bound amyloid less avidly than standard lithium carbonate and more effectively raised lithium levels in non-plaque brain tissue in mice. Administered at physiological doses, lithium orotate not only prevented but, in older animals, partially reversed amyloid and tau pathology, reduced neuroinflammation, and improved performance on memory tasks [1].
“One of the most galvanizing findings for us was that there were profound effects at this exquisitely low dose,” said Yankner [3].
Beyond Alzheimer’s
The protective effects of physiological lithium replacement extended to normal brain aging. In wild-type mice followed from middle age to 24 months, lithium orotate treatment preserved dendritic spines, prevented memory decline and maintained microglial capacity to clear amyloid. These findings, the authors note, align with observational studies linking higher lithium content in drinking water to lower rates of dementia [1].
“Lithium turns out to be like other nutrients we get from the environment, such as iron and vitamin C,” Yankner said. “It’s the first time anyone’s shown that lithium exists at a natural level that’s biologically meaningful without giving it as a drug [3].”
The paper also points to correlations in older adults without cognitive impairment: higher brain lithium levels were associated with better working memory and higher scores on the Mini-Mental State Examination. While observational and correlative, these data suggest lithium homeostasis could be a measurable and modifiable determinant of resilience to cognitive decline [1].
“My hope is that lithium will do something more fundamental than anti-amyloid or anti-tau therapies, not just lessening but reversing cognitive decline and improving patients’ lives,” he said [3].
Balancing act
The authors caution that while the preclinical data are strong, translation to humans will require careful dose-finding and safety monitoring; low-dose lithium carbonate has shown mixed results in small Alzheimer’s trials, potentially due to its higher amyloid binding [1]. Lithium orotate’s pharmacokinetics in humans remain to be studied in detail.
If future studies confirm these findings in humans, lithium could shift from being a specialist’s tool in psychiatry to a broadly relevant micronutrient for brain health; the challenge will be determining how to maintain optimal brain lithium across a lifetime without tipping into harmful excess. This is a nuanced therapeutic landscape – one where the measure of success will be in milligrams and micromolar concentrations, not the blunt force of pharmacological dosing.
[1] https://www.nature.com/articles/d41586-025-02255-w
[2] https://pubmed.ncbi.nlm.nih.gov/2218531/
[3] https://hms.harvard.edu/news/could-lithium-explain-treat-alzheimers-disease
