“Lithium deficiency is … a potential common mechanism for the … degeneration of the brain that leads to the onset of Alzheimer’s disease.”
That’s the conclusion from a groundbreaking study just published in the journal Nature [1]. Alzheimer’s disease is one of the leading causes of death, but we’re still unsure about exactly what drives it. This compelling research points to a possible new mechanism. And this raises the potential of giving us a novel way to both detect and treat this debilitating disease.
So let’s unpack the study and consider whether it’s time to start taking lithium supplements.
Table of Contents
The New Study
We already have a decent grasp of the process of brain decay that happens with Alzheimer’s disease. It involves two basic mechanisms. First, there’s the buildup of sticky protein fragments called amyloid plaques, which form outside brain cells and disrupt communication. Second, there are twisted tangles of a protein called tau that build up inside neurons, disrupting normal function. Together, these problems trigger inflammation and, eventually, cell death.
What we aren’t as sure about is why this process happens and what we can do to stop it. We’ve learned about some genetic variations that make individuals more at risk of developing Alzheimer’s. But the environmental factors are poorly understood [1].
And these are obviously crucial—because while we can’t change our genes, we can take steps to modify our environment, if we know what those risk factors are.
Researchers have identified several environmental factors that seem to play a role in Alzheimer’s disease. One of these is the levels of metals in the brain [1]. Previous studies have mostly looked at the toxic effects of too much iron or copper. But the disruption of normal levels of important metals hasn’t been explored much [1].
That’s what researchers in this latest study set out to investigate—and they made a startling discovery.
Researchers examined human brain tissue samples from people who had died. The samples came from individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer’s disease (AD). They measured 27 different metals in these samples [1].
One metal stood out: lithium. Its levels were much lower in the brains of those with MCI or Alzheimer’s disease [1].
Interestingly, blood lithium levels looked normal in those with cognitive decline. So the problem wasn’t systemic—it was localized in the brain [1].
Researchers had some reason to suspect the amyloid plaques were involved, so they specifically examined lithium levels within these plaques. They found lithium was concentrated in the plaques, and the levels were even higher in those with Alzheimer’s than those with mild cognitive impairment [1].
This suggested a plausible mechanism: the amyloid plaques absorb lithium, depleting it from surrounding brain tissue.
This led to an important question: is lithium deficiency a causal factor in Alzheimer’s disease progression?
To find out, researchers turned to mice. They reduced lithium intake by 92% in their diets. Some mice were genetically modified to develop plaques early. In these mice, plaques formed sooner and grew faster when lithium was restricted. Normal mice also showed increased levels of the proteins that form plaques when on the low-lithium diet [1].
Not only that, the low-lithium diet promoted tau tangles as well [1].
And the negative effects didn’t stop there. The lithium-deficient mice also showed increased inflammation, microglial activation, loss of synapses, axons, and myelin, and cognitive decline [1].
This paints a picture of a vicious cycle: amyloid plaques absorb lithium, depleting it from the brain. That lithium deficiency, in turn, accelerates plaque formation and other Alzheimer’s-related damage.
And here’s the deeper mechanism: as plaques sequester lithium, this depletes lithium in healthy brain regions. That drop impairs microglial clearance of amyloid plaques—allowing more plaques to form. It’s a classic positive feedback loop [1].
The Broader Context
The implications of this are huge. The researchers believe this could be a key mechanism that drives Alzheimer’s disease. But we need to be cautious. The study relied heavily on mouse models and extremely low dietary lithium, which might not reflect real-world scenarios.
So do human studies support this?
There’s evidence going back decades that lithium affects cognitive function. High-dose lithium is a long-standing treatment for bipolar disorder, and some of my patients have been prescribed it.
More recently, there have been observational studies linking lithium to cognitive benefits. A Danish population study of over 73,000 dementia patients and 733,000 controls found an inverse relationship between lithium in drinking water and dementia incidence [2].
Another study followed up with participants from an earlier clinical trial on lithium for mild cognitive impairment. Over a decade later, those who had taken lithium scored better on cognitive performance tests than those who hadn’t [3].
What about clinical trials?
Two early trials found no cognitive improvement with lithium. However, this may have been because they used lithium carbonate, a form that—based on newer data—may be ineffective due to its high binding to amyloid plaques [1].
Three subsequent trials used lower serum concentrations (0.25–0.5 mEq l−1) and found that lithium reduced cognitive decline [1].
A meta-analysis comparing lithium and the Alzheimer’s drug aducanumab found that lithium was significantly more effective at preventing cognitive decline [4].
Implications
All of this naturally raises the question: should we supplement with low-dose lithium? What are the risks, the benefits—and what form of lithium is best?
The original study offers some clues. Researchers noticed lithium becomes bound to amyloid plaques, limiting its availability to the brain. So they looked at whether lithium orotate, a different form than the clinically-used lithium carbonate, might avoid being trapped in plaques.
They tested both forms in mice. Both forms raised blood lithium levels similarly. But in the brain, lithium carbonate led to high lithium levels within plaques, while lithium orotate increased lithium in healthy brain regions [4].
And this made a major difference. Lithium orotate almost completely blocked plaque formation and tau accumulation. Lithium carbonate had no significant effect [4].
Even more exciting, lithium orotate significantly slowed disease progression, whereas lithium carbonate did not [4].
The form of lithium clearly matters. The researchers suggest this might explain why earlier trials using lithium carbonate failed—they were using a form that binds too easily to amyloid plaques [4].
So here’s what we’re left with:
- Lithium deficiency might be a key driver in the development of Alzheimer’s.
- Increasing lithium intake—particularly with lithium orotate—might help slow or prevent disease progression.
-
The form of lithium is crucial. Lithium orotate appears to be far more effective at reaching healthy brain tissue.
That sounds like a strong case for taking low-dose lithium orotate. But we should pause before jumping in.
Here’s why:
1. The research is still limited, especially in humans. While animal studies and some human data are promising, we need larger, long-term trials to draw firm conclusions.
2. We don’t yet know the optimal dose for cognitive protection. Too much lithium, even at modest levels, can have serious side effects, especially at higher doses used in psychiatric treatment. While low-dose use is likely safer, risks still exist.
3. We already get some lithium from diet and water.
Remember the Danish study—it was based on naturally occurring lithium in water supplies. And one study found that certain vegetables—like bulbous vegetables and fructose solano vegetables—can have very high lithium concentrations [5].
- Bulbous vegetables: Li > 13.47 mg/kg
-
Fructose solano vegetables: Li > 11.33 mg/kg
4. These levels were high enough to raise concerns about excessive intake.
If you live in an area with lithium-rich water or eat a lot of high-lithium foods, you may already be getting enough. That’s one reason I haven’t included lithium in MicroVitamin yet.
The bottom line? We need better clinical evidence before making strong supplement recommendations. I’ll be keeping a close eye on future developments. But for now, caution is warranted.
