Lithium Orotate and Alzheimer’s: Harvard Study Reveals a Breakthrough in Brain Aging

Alzheimer’s disease, the most common severe form of dementia that afflicts more than 10% of American seniors, is likely the most widely feared disease, robbing them of their cognitive abilities and, ultimately, their sense of self. But allow yourself to dream for a moment. Imagine that a drug we’ve been routinely using for many decades has a secret power, the ability to slow the progression of AD, or to stop it before it has a chance to get its hooks into us in the first place.

The dream could turn out to be true. The drug in question is lithium, a soft, silvery mineral, which is found in small amounts in the water we drink and the plants we consume. As most of us probably know, lithium, in the form of lithium carbonate, is a time-tested therapy for bipolar disorder. In fact, lithium was known to be an effective treatment for mental disorders going all the way back to the 19^th century when chemists were able to isolate the element in mineral spring waters. (The ancient Greeks had picked up on mineral water’s therapeutic effect on the brain centuries before.)

The evidence that lithium could have broader brain health applications than bipolar disorder has been steadily growing since the early 2000s. But it really didn’t grab the attention of the wider medical world until the publication of an article by a group of Harvard researchers in Nature in early August: “Lithium deficiency and the onset of Alzheimer’s disease.” Here again a case of a familiar drug being repurposed (and prescribed “off-label” without a new FDA disease indication) for a much broader health impact -- the same story I told in my previous post about the anti-cholesterol drug Zetia (ezetimibe) showing potential as a drug to combat, yes, AD.

But the lithium story is, in a way, even better. Lithium has to be combined with something else to make it available to the body, usually a salt. The pharmaceutical industry came up with lithium carbonate because it was easy to formulate, and it became the standard bipolar treatment. But lithium carbonate doesn’t cross the blood-brain barrier easily so large doses, often well over a thousand milligrams daily, had to be used. With that came significant toxicity, especially in the liver and kidneys, with older patients being more vulnerable. 

But the Harvard team combined lithium with orotate, which contains less elemental lithium (4.7% vs. 18.7%) but enters the brain, in mice at least, in therapeutic concentrations at about  1/1000th the dose of lithium carbonate. It also avoids sequestration  (more on this below) enhancing its therapeutic effects in “micro-doses” of  2-10 mg, far lower than the hundreds or thousands of milligrams typically used to treat bipolar disorder.

The Harvard researchers have further consolidated the evidence that lithium plays a vital everyday role in our brains. They also discovered that lithium levels go down with age and they are especially low in people with mild cognitive impairment and with dementia/AD. That corresponds with older epidemiological research that found a strong association between higher levels of lithium in the environment and better mental health, and the inverse, less lithium, worse mental health. Which is why, even though we don’t yet have any clinical trials measuring the safety and efficacy of lithium orotate, the idea of supplementing with it to push back against AD, and more broadly, to support the aging brain, makes so much sense.

The old AD story was all about developing drugs to clear the body of the amyloid plaques and tau tangles that disrupt cognitive function, an effort that to date has yielded deeply disappointing results. The ten years of research that went into the Nature paper, integrating in vitro human cell studies with mouse models, tells a new story that in a way subsumes the old one. To wit: one of lithium's most valuable functions in our brains is inhibiting GSK-3beta, a protein kinase that drives excess amyloid production and phosphorylation of tau protein which, in turn, promotes the growth of those sticky amyloid-tau tangles. Early in the AD process, lithium becomes sequestered by amyloid, making it less available to perform its GSK-3beta-inhibiting function. But, in the mouse models, the supplemental lithium orotate, a less amyloid-friendly form, evades the trap, putting the brakes on the amyloid/tau vicious circle before it spins out of control. And, yes, the mice had their memory restored.

Could lithium be a crucial upstream player in the disease process or does it play a smaller, more complementary role? We don’t yet know but the recent science is starting to make a persuasive case that it could be a central factor. 

What I do know is that lithium opens a more promising way to look at the aging brain. Lithium positively impacts a variety of mechanisms. It activates the WNT/beta-catenin system, which controls stem cell renewal/repair and in the brain promotes cell growth – neurogenesis – in the hippocampus and repair of the synapses. It supports autophagy, helping to clear out misfolded proteins and damaged mitochondria, providing another brake on plaque accumulation. It boosts brain growth factors like BDNF and VEGF; it tamps down inflammatory cytokines like TNFalpha, inflammation, yet another engine of neurological decline.

The short precis of the Harvard work is that lithium orotate not only addresses amyloid/tau, the AD bad actors we’re most familiar with, but it also supports overall brain resiliency, which helps buffer the effects of any age-related pathological process, whether you label it AD or not.  

I’m also alert to the potential of a “multi-modal” approach. One could, for instance, combine lithium orotate with tools that are already in my longevity toolbox, drugs and supplements that promote autophagy and help clear out senescent cells, which would complement lithium’s anti-inflammatory effects.

One could do a lot of things. But, absent clinical trials, I don’t think we’re at the point where we’re prescribing lithium orotate to anyone who’s  worried about AD. (I said the same thing about Zetia.) However, if you’re at elevated risk for AD, then I think the risk/reward calculus changes. At least, it should. For my patients who carry the single copy of the APOe4 gene that roughly doubles AD risk, or has an elevated p-tau217 level predicting high likelihood of developing AD, lithium orotate is on the table. (I am an ApoE 3/4 and I take a daily 10 mg. dose.) If they’ve got the rarer double copy of the mutation that increases risk by as much as 15-fold I strongly encourage it. And there are other ways to predict risk: performance on functional cognitive tests, especially over time; blood tests; MRI which can capture abnormal brain volume shrinkage.

A familiar old line used to be, ‘I don’t want to find out if I’m at higher risk for AD because I can’t do anything about it.” That was never true. We know that stricter adherence to a healthy lifestyle – exercise, diet, good sleep – can move the odds in your favor. But with lithium orotate possibly heralding a new era of geroprotective therapies, there really is no excuse not to get a diagnostic picture of how well or not so well your brain is aging. The more you know, the better you can address your particular risk factors. Of course, it would be a huge help if we had those lithium orotate randomized controlled trials on the near horizon, less likely now that the current Administration is trying to gut the NIH. But that’s a pathology beyond the scope of this post.

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Radanovic M, Singulani MP, De Paula V de JR, Talib LL, Forlenza OV. An Overview of the Effects of Lithium on Alzheimer’s Disease: A Historical Perspective. Pharmaceuticals (Basel). 2025;18(4):532. doi:10.3390/ph18040532

Aron L, Ngian ZK, Qiu C, et al. Lithium deficiency and the onset of Alzheimer’s disease. Nature. Published online August 6, 2025:1-10. doi:10.1038/s41586-025-09335-x