Lithium and Its Potential Protection from Alzheimer's Disease

A new, elegant study reawakens the prospects for this metal, and specifically lithium orotate

“Lithium powers our phones, laptops, and electric vehicles. My guess is the brain might have utilized this unique electrochemistry before we did.”—Bruce Yankner, senior author of the new report

If you’ve been reading recent Ground Truths posts, you’ll know I have been focusing on Predicting and Preventing Alzheimer’s Disease, and the Breakthrough Blood Test for Alzheimer’s Disease. This week the prospects for reducing the risk of Alzheimer’s had another advance with a new and impressive study published in Nature by Bruce Yankner and colleagues at Harvard Medical School. In this edition of Ground Truths, I’ll review the key background on Lithium and what we’ve just learned from the new report. I’ll divide this into 3 questions: (1) What Did We Know?; (2) What We Know Now; and (3) What’s Next?

1. What Did We Know About Lithium and Alzheimer’s Disease?

Despite lack of knowing its mechanism of action, lithium use for bipolar disorder (BD) and psychiatric conditions dates back to the late 1800’s and —lithium carbonate— was approved for BD by the FDA in 1970. Its use is associated with a range of serious side effects, including neurologic, kidney and thyroid, establishing it as a medication with a narrow therapeutic window. From 3 different lines of evidence in clinical research, there was support for a potential lithium benefit for relative protection against Alzheimer’s and dementia (~80% of dementia is Alzheimer’s) or preservation of cognitive function.

—Randomized Trials

There have been 4 small placebo-controlled randomized trials, 3 of which were included in a meta-analysis, shown below for lithium’s benefit on cognitive function. Besides being very small (40 to 90 participants), the trials varied for inclusion criteria, length of drug treatment (10 weeks to 15 months), endpoints, levels of blood lithium achieved, and many other factors. The direction was towards benefit for all 3 trials, but only one on its own (Nunes 2013) was statistically significant.

A more recent randomized, double-blinded, placebo-controlled trial published in 2019, again with a small sample of 61 participants, using lithium carbonate at low doses for 2 years, also supported the finding with less conversion from mild cognitive impairment to dementia by lithium (Figure below, NB: P=0.06 is not significant at the 0.05 level; other measures of cognitive function were statistically significant for lithium’s advantage).

Notably, there was an increase in the lithium group concentration of amyloid-β in the cerebrospinal fluid vs placebo, suggesting the drug was helping to promote its clearance.

Another randomized lithium trial at the University of Pittsburgh of 80 participants called LATTICE (Lithium as a Treatment to Prevent Impairment of Cognition in Elders) with 2-year treatment, PET and MRI imaging, has been completed and the results are currently pending.

—Evidence in Bipolar Disease

A report from Denmark of nearly 5,000 patients with BD, of whom 30% were treated with lithium, was associated with statistically significant protection from dementia, a link not seen with anticonvulsants, antidepressants, or antipsychotics. (Table below). It has been noted that lithium’s efficacy is diminished in older people with BPD, which may have something to do with the amyloid sequestration mechanism described below.

—Evidence from Drinking Water Exposure

Another nationwide study from Denmark assessed lithium exposure in the water for over 73,000 people who developed dementia and over 730,000 controls. As seen in the Table below, the higher the mean lithium exposure, the more relative protection.

2. What We Know Now

The new paper took an agnostic approach to metals in the human brain, assessing the concentration of 27 of them, and finding only that lithium (Li) stood out in both people with mild cognitive impairment (MCI) and Alzheimer’s disease (vs individuals no cognitive impairment, NCI).

Indeed, the concentration of lithium in human brains were markedly different (ratio of cortex to blood or in brain tissue,) as shown below. Notably, the levels of lithium in the brain from people with intact cognition is 1,000X lower than what are achieved with lithium treatment for BD.

With that background a series of experiments in mice with either lithium deficient diet or lithium repletion were undertaken, in Alzheimer model mice and aged (wild-type) mice, along with the effects of these manipulations on memory, learning, inflammation and related changes in brain cells and tissue.

The principal findings can be summarized:

1. Amyloid plaque-in the brain binds avidly to lithium and sequesters it (left panel below). That steals the lithium from non-plaque tissue and reduces its function. When the right lithium salt preparation is given (lithium orotate) that doesn’t get sequestered by amyloid, the microglia cell function is improved to clear amyloid-β (right panel below).

   

2. A lithium-deficient diet in the Alzheimer model mouse was pro-inflammatory with increased activated microglia (Figure also shown at the top of this post), marked accumulation of amyloid-β, and phosphorylated tau protein, loss of synapses, axons, myelin, worsened cognitive function and memory.

   

3. Finding a lithium salt that was much less likely to form ions and get sequestered by amyloid-β, turned out to be lithium orotate, markedly better than lithium carbonate, the drug that has been used in BD and that undergone previous clinical trials for cognitive function and progression to Alzheimer’s disease.

   

4. When compared with lithium carbonate, lithium orotate better prevented accumulation of amyloid-β, tau-phosphorylation, neuroinfalmmation and cognitive parameter decline.

5. Lithium orotate given to aged wild-type mice (not the Alzheimer’s model mice) reverted their memory to young adult (6-month) level, along with object recognition and maze tasks.

6. SIngle-nucleus RNA sequencing showed parallel changes of gene expression between the lithium diet deficient mice and human brain samples with Alzheimer’s disease. The enzyme glycogen synthase kinase GSK3β is activated and expressed by endogenous lithium deficiency. An inhibitor to this kinase may also provide protective effects.

   3. What’s Next?

   The new study is the most impressive neuroscience of lithium published to date. It is comprehensive, mechanistic, and brings together compelling human and mice data (the latter from both the Alzheimer’s model and aging organism). The work also led to the discovery of a far better lithium salt that reduces the likelihood of being trapped by amyloid-β, following up the finding that sequestration is foundational to lithium’s effect. The point that very low doses of lithium would be expected to achieve salutary effects in humans is especially noteworthy, given the toxicity of lithium carbonate at high doses used in BD. Importantly, this extensive work would not have been possible without the support by multiple NIH grants now being subject to profound cuts, no less $2.6 billion specific to Harvard .

   The outgrowths of the new study go well beyond reduced brain inflammation and promoting amyloid-β clearance to reduce progression to Alzheimer’s disease, raising the question should lithium levels be assessed as a risk factor and might this also be extended to other neurodegenerative diseases, such as Parkinson’s.

   Lithium orotate is not naturally found in significant amounts in common foods. Should people start taking lithium orotate, such as the low dose of 5 mg now, widely available as an unregulated supplement? The answer is no, even though we’d anticipate it would be safe, without worrisome side effects as seen with considerably higher doses of lithium carbonate used for BD. Yes, it’s tempting, with the body of evidence presented here that exceeds supplements in common use, but we need a clinical trial to prove that the new study translates to a human benefit. If lithium orotate does work, we don’t know the right or optimal dose. Even 10 mg would be a huge dropdown from the usual dose for lithium carbonate, which for BD in adults is between 600 to 1,800 mg/day. The amount of elemental lithium in lithium orotate is approximately 1/5th of lithium carbonate. So doses of orotate between 5 and 10 mg may be insufficient to achieve the effect (10 mg of lithium orotate is equivalent to about 0.4mg of elemental lithium).

   As I previously discussed with p-tau217 and other blood markers, along with pace of aging brain clocks (using proteomics), it would be straightforward to do a randomized trial and see whether these surrogate metrics are favorably modulated by lithium orotate versus placebo. We hope to initiate such a randomized trial in the near future that would help illuminate whether low dose lithium orotate has efficacy in people.

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