Meta-analysis finds no reliable cognitive benefit from conventional lithium salts in mild cognitive impairment or Alzheimer's disease. Digest
Laboratory and animal studies suggest lithium could protect the brain from cognitive decline and Alzheimer's disease, but results from human trials have been mixed. To clarify the picture, researchers combined data from multiple clinical trials to test whether pharmaceutical lithium salts have meaningful benefits for brain health.
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The authors systematically reviewed and meta-analyzed six randomized, placebo-controlled trials (435 participants) that compared lithium supplementation with placebo in studies lasting roughly 10 weeks to 24 months. All participants had either mild cognitive impairment, a stage of measurable decline that can precede dementia, or Alzheimer's disease. The main outcome was change in cognition, and the tested lithium salts were: lithium carbonate, lithium sulfate, and lithium gluconate.
- When results from all six trials were combined, lithium was similar to placebo for cognitive outcomes.
- In the primary analysis, which prioritized the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), the average difference between lithium and placebo was small and could not be confidently attributed to the treatment rather than chance.
- Follow-up analyses that relied on different cognitive measures or prioritized different tests reached the same conclusion and showed no consistent cognitive benefit from lithium.
- Measures of behavioral and psychological symptoms of dementia, such as agitation and related behavioral problems, were similar between lithium and placebo groups.
- Subgroup analyses found no differences based on diagnosis (mild cognitive impairment vs. Alzheimer's disease), study duration, lithium dose, or lithium salt type.
- One study suggested a stronger effect from lithium, but it was judged to be at high risk of bias, making its result unreliable.
Lithium's biological effects may depend strongly on its chemical form and how it behaves in the brain. Studies in animals show that lithium can stick to amyloid-β, the protein that forms plaques in Alzheimer's disease. When this happens, lithium becomes trapped inside plaques instead of remaining available to brain cells, where it could help regulate inflammation, communication between neurons, and limit harmful changes to tau, a structural protein that helps stabilize neurons. Commonly tested lithium forms, especially lithium carbonate, appear more likely to bind to amyloid plaques in this way. By contrast, laboratory and animal studies suggest that lithium orotate, a different chemical form, may enter brain cells more easily and avoid plaque binding.
Importantly, the clinical trials analyzed here did not test lithium orotate, only carbonate, sulfate, and gluconate. As a result, the study supports the conclusion that standard lithium supplements do not slow cognitive decline in people with mild cognitive impairment or Alzheimer's disease, while leaving open the possibility that other lithium formulations could be more effective. In Q&A #69, I discuss the benefits and risks of low-dose lithium supplementation.