Lithium Deficiency May Spur Alzheimer's, Guide Treatment

Medscape

a day ago

Lithium, long prescribed for bipolar disorder and as an adjunct in depression, is essential for brain resilience, and new research suggests that deficiency of the mineral in neural tissue may contribute to Alzheimer's disease (AD).
For the first time, investigators found that lithium is sequestered by amyloid plaques in AD, depleting its availability in neural tissue. In addition, they found that a novel lithium-based compound engineered to bypass plaque binding reversed synaptic and cognitive deficits in mouse models and has the potential to restore memory
In addition, analyses of human brain tissue showed that loss of lithium was one of the earliest changes leading up to AD. In mice with lowered lithium levels, researchers found similar accelerated brain pathology and memory decline.
Amyloid-beta (Aβ) plaques in the brain are a hallmark of AD. When they develop early in the disease, they bind to lithium, inhibiting uptake of the mineral in the brain and lead to the reduced lithium levels observed in the study.
Researchers also identified a plaque-evading lithium salt that, when administered to mouse models with AD, was associated with significantly reduced AD-type pathology and improved memory.
'We found that endogenous lithium in the brain changed during aging, and this could be recapitulated in mouse models of the disease,' coinvestigator Bruce A. Yankner, MD, Department of Genetics, Harvard Medical School, Boston, told Medscape Medical News.
'Importantly, by simply depleting [lithium] from the mouse diet, we found that it had protean effects, changing the cell biology of the aging brain, the pathology of Alzheimer's disease, and parameters of neurocognitive function,' Yankner added.
The findings were published online on August 6 in Nature .
A 10-Year Journey
About 10 years ago, the same researchers found that the neuron-restrictive silencer factor, the transcription factor (REST), which was previously established as a central regulator of neural development, was involved in the brain's response to aging and AD, Yankner said.
A component of this discovery was the regulation of REST by the Wnt signaling pathway. Lithium is a classic approach to activating Wnt signaling, he added.
'While using lithium in this context, we were impressed with its ability to reduce all the various neuropathologic and cellular changes in animal models of Alzheimer's,' Yankner said. 'I wondered whether lithium itself might be part of the disease mechanism.'
So the Yankner and his team set out to determine whether there might be endogenous lithium in the human brain.
Using high-sensitivity inductively coupled plasma mass spectrometry adapted for human brain and blood samples, researchers measured 27 abundant and trace metals in the brains and blood of individuals with normal cognition, amnestic mild cognitive impairment (MCI), or AD.
To Yankner's surprise, of all the major and trace metals analyzed, only lithium was significantly reduced in the prefrontal cortex of participants with MCI or AD. It also had the lowest P value of any metal.
'Other metals changed in AD, but they did not show significant changes in MCI, the earliest stage of memory loss,' Yankner said.
In addition, every case of MCI and AD showed significant concentrations of lithium in Aβ plaques.
'Together, these results indicate that endogenous [lithium] homeostasis is perturbed in the brain in MCI and AD,' the investigators wrote.
Lithium as a Potential Treatment?
The researchers also found cortical distribution of endogenous lithium in Aβ precursor proteins in mice. Reducing cortical lithium by 50% not only increased Aβ and phosphor-tau in the animal models but also increased inflammatory microglial activation and cognitive decline.
The use of lithium orotate, a lithium salt with reduced amyloid binding, led to reduced pathological changes, reduced memory loss, and restored microglial function, and may be 'a potential approach to the prevention and treatment of AD,' the researchers wrote.
Lithium toxicity is a concern for older patients who receive highly concentrated formulations of the drug to treat psychiatric illness. But lithium orotate is significantly less concentrated and mice treated with the compound showed no evidence of toxicity.
Yankner said that, from a clinical standpoint, his team will now advance on two fronts.
First, they are exploring ways to detect lithium deficiency early, either by measuring it directly or through surrogate markers. Second, they aim to identify subpopulations most likely to benefit from lithium based on clinical and biochemical criteria.
'As a neuroscientist, I am excited about exploring the physiology of lithium in the brain. Our single nucleus RNA sequencing data suggests that there are significant effects of endogenous lithium on all brain cell types we examined,' Yankner said.
'I believe that future studies may uncover some very interesting biology,' he added.
Several Limitations
Commenting on the study for Medscape Medical News, Ozama Ismail, PhD, director of Scientific Programs at the Alzheimer's Association, said a major limitation to interpreting the findings is the use of a mouse model.
'Animal models do not directly replicate Alzheimer's in humans; rather, they can provide some insights into the biology of disease progression and development. The mouse models have been modified to accumulate amyloid beta, a hallmark protein that builds up in the brains of people with Alzheimer's,' said Ismail, who was not involved with the research.
He noted that studies in mouse models represent a crucial early step in the development of any therapeutic intervention.
'However, before we can know the exact role of this metal in Alzheimer's biology, much more research is needed to understand the effect of lithium levels in the brain in people from a wide variety of communities and different health status,' he said, adding that large clinical trials are also needed to understand whether lithium really can be therapeutic for AD.
Ismail emphasized the importance of investigating all potential therapies, noting that, as with other major diseases, effective treatment for AD will likely require a combination of medications and lifestyle interventions.
Regarding the human analyses in the current study, he emphasized that the findings do not clarify the mechanism behind the reduced lithium levels — whether the disease itself causes the decrease or another factor indirectly lowers them.
As for the human analyses in the current study, he pointed out that the findings do not explain the mechanism driving the reduced lithium in these individuals — whether the disease itself is causing the reduction or if another factor may be indirectly lowering the levels.
'This is where the animal study comes in, as it tries to get to the mechanism, and suggests that when lithium is lower, amyloid is higher. This might be due to immune changes or metabolic changes, and we need more research to understand this better,' Ismail said.