The Lithium Link to Alzheimer’s: Potential for Prevention and Treatment

A landmark study from Harvard Medical School has uncovered a surprising player in the early stages of Alzheimer’s disease: lithium. Commonly prescribed for bipolar disorder in pharmacologic doses, lithium at trace, naturally occurring levels in the brain appears to play a protective role in aging and cognitive health. According to the research, published in Nature, declining lithium levels may not just accompany Alzheimer’s pathology—they may actively contribute to it.

The investigators found that lithium was uniquely depleted in the prefrontal cortex—the brain region crucial for executive function and memory—in individuals with mild cognitive impairment (MCI), a clinical harbinger of Alzheimer’s disease (AD). In both MCI and AD cases, lithium was sequestered into amyloid plaques, rendering it bio-unavailable. No other metal among the 27 surveyed showed such a consistent and significant depletion, underscoring lithium’s potential specificity as an early biomarker and driver of disease.

This deficiency was not just a downstream effect of brain deterioration. When mice were placed on a lithium-depleted diet, they exhibited accelerated deposition of amyloid-beta and phosphorylated tau—hallmarks of AD pathology—as well as synapse loss, microglial inflammation, and memory impairment. These changes emerged rapidly, within weeks of dietary lithium restriction, even in mice without genetic predisposition to Alzheimer’s.

At the molecular level, lithium deficiency disrupted key cellular pathways involved in neuroprotection and synaptic maintenance. Using single-nucleus RNA sequencing, the researchers showed that lithium-depleted brains displayed transcriptomic signatures strikingly similar to those seen in human Alzheimer’s cortex—including changes in microglia, neurons, oligodendrocytes, and astrocytes. The microglia, in particular, adopted a reactive, pro-inflammatory state, expressing genes linked to Alzheimer’s risk such as TREM2, APOE, and BIN1.

Importantly, the study identified the enzyme GSK3β as a likely mediator of these effects. GSK3β, which promotes tau phosphorylation and impairs synaptic signaling, was upregulated in lithium-deficient brains. Inhibiting GSK3β reversed many of the pathological features induced by lithium loss, including impaired amyloid clearance and cognitive deficits.

The implications go beyond identifying a new disease mechanism. The research also introduces a potential therapeutic candidate:lithium orotate. Unlike conventional lithium carbonate, lithium orotate binds poorly to amyloid and thus remains more bioavailable in the Alzheimer's-affected brain. In mouse models, low doses of lithium orotate—notably within the range of naturally occurring lithium levels in humans—prevented or even reversed plaque formation, tau accumulation, synaptic loss, and memory impairment. Lithium carbonate, by contrast, was largely ineffective at these same doses.

These results offer a new paradigm for Alzheimer’s prevention and early intervention. Rather than attempting to eliminate amyloid plaques after they form, the study suggests that preserving lithium homeostasis might delay or even prevent the pathological cascade from starting. This could be especially impactful in the preclinical stage of Alzheimer’s, which can span years or decades before symptoms arise.

The findings also echo previous epidemiological work from Denmark showing an inverse relationship between lithium levels in drinking water and dementia incidence. Now, this population-level signal has a mechanistic foundation—one that includes changes in gene expression, protein abundance, and cognitive behavior.

Crucially, lithium orotate did not produce detectable toxicity in aged mice, a major consideration given the known risks of lithium therapy at pharmacologic doses, such as kidney and thyroid dysfunction. In both Alzheimer’s-prone and normally aging mice, chronic low-dose lithium orotate preserved synaptic density, reduced neuroinflammation, and improved memory function.

As Alzheimer’s research continues to wrestle with failed amyloid-targeting therapies, this study adds a compelling new layer—shifting attention to a naturally occurring neuroprotective mechanism that may be quietly eroding in the early stages of disease.