Lithium could help treat Alzheimer's
People with the neurodegenerative condition have low levels of the metal in their brain which the study revealed, for the first time, is needed for normal brain function.
Experiments in mice found that when a novel form of lithium was given to animals with Alzheimer's disease, it reversed the symptoms, even in severe cases.
The scientists now hope to further investigate lithium as a potential treatment in humans with clinical trials.
'These findings reveal physiological effects of endogenous lithium in the brain and indicate that disruption of lithium homeostasis may be an early event in the pathogenesis of Alzheimer's disease,' the scientists write in their study.
'Lithium replacement with amyloid-evading salts is a potential approach to the prevention and treatment of Alzheimer's disease.'
Lithium's role in the body has long remained a mystery but it has been used as a medication for mental health conditions such as bipolar disorder and schizophrenia for decades.
A decade-long study saw Harvard scientists analyse the brains of deceased donors at various stages of Alzheimer's disease, as well as in people with no disease when they died.
They found lithium to be the only one of 27 metals to be at lower levels in cases of disease.
Experiments in both humans and mice brain samples found that amyloid plaques, the protein which develops in cases of Alzheimer's and causes disease, pulls lithium out of brain cells.
In healthy brains, the lithium, which naturally has a positive charge, stays in the cells and helps maintain normal function.
But in brains with amyloid, which is naturally negatively charged, the lithium is attracted to the disease-causing plaque and pulled out of the cells.
This depletion triggered the brain's immune defence cells to go awry and caused inflammation and an inhibited ability to break down and clear out the toxic amyloid, which suffocates neurons and leads to cognitive decline and Alzheimer's.
Scientists have investigated lithium as a possible treatment for Alzheimer's previously but found existing medications in the form of lithium carbonate to be ineffective and also prone to significant side effects.
The Harvard team looked for lithium compounds which are not strongly positive in charge that would be impervious to amyloid and therefore more likely to stay in the cells and not be pulled out.
The compound lithium orotate was found to be ideal and in mice studies reversed the course of disease, alleviated symptoms and restored memory.
This form of lithium was given in small doses to animals to mimic the natural level of the metal and analysis found it 'almost completely prevented' amyloid from settling in the brain.
In older mice with severe disease, the treatment 'was highly effective at reducing amyloid deposition and tau accumulation'.
It also 'almost completely reversed the memory loss', the scientists write, whereas the existing lithium medicine had no impact. Lithium orotate also improved learning and spatial memory in old mice with severe amyloid.
The authors are reluctant to draw conclusions for humans from these rodent experiments but say this new lithium medicine could be a viable route for future drug studies.
Current Alzheimer's drugs such as donanemab and lecanemab do not improve a patient's condition but slow down disease progress.
However, these come at significant cost as well as the risk of serious side effects such as brain bleeds and swelling.
Neither was approved by the National Institute for Health and Care Excellence for use on the NHS despite being deemed effective and safe by the Medicines and Healthcare products Regulatory Agency.
Results 'very encouraging'
No drug has yet been discovered that can actually improve a patient's condition and reverse the condition of Alzheimer's.
'You have to be careful about extrapolating from mouse models, and you never know until you try it in a controlled human clinical trial,' study author Prof Bruce Yankner, professor of genetics and neurology at Harvard, said.
'But so far the results are very encouraging. What impresses me the most about lithium is the widespread effect it has on the various manifestations of Alzheimer's. I really have not seen anything quite like it in all my years of working on this disease.'
The study is published in the study Nature and in an accompanying opinion piece, Prof Ashley Bush from the University of Melbourne, who was not involved in the research, said the work of the Harvard team exposes 'a possible contributor to Alzheimer's disease and a potential non-conventional therapeutic target'.
The work could also lead to improvements for how lithium is used in mental health conditions, she believes, especially in older patients.
'Apart from the implications for treating Alzheimer's disease, the data invite a re-evaluation of lithium-salt variants as treatments for older adults with bipolar disorder,' she writes.
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