Alzheimer’s progression linked to lithium levels in the brain

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].