Summary:
This study was an experimental laboratory study that analysed human brain tissue and used mouse models of Alzheimer’s disease (AD) to investigate the role of naturally occurring lithium in brain health, ageing, and cognitive decline. The researchers found that people with mild cognitive impairment, which can occur before AD develops, had lower lithium levels in their brains than people without cognitive impairment. Of all the metals examined, lithium was the only one that was significantly reduced. To investigate the importance of lithium, this study reduced lithium levels in the diets of healthy mice and mice genetically predisposed to AD. Lower brain lithium levels were associated with increased build-up of amyloid and tau, proteins that form harmful tangles in the brain in AD. Lithium deficiency was also linked to increased inflammation, loss of communication points between nerve cells, damage to nerve fibres, loss of the protective coating around nerve fibres, and faster declines in cognition. Overall, this study suggested that naturally occurring lithium may help maintain normal brain function and support memory during ageing, and that disruption of lithium balance in the brain may be an early event in the development of AD. The results also suggest that lithium-based treatments may have potential for preventing or slowing disease progression.
Read the Complete Article >
Abstract:
The earliest molecular changes in Alzheimer’s disease (AD) are poorly understood1,2,3,4,5. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, Li was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to AD. Li bioavailability was further reduced in AD by amyloid sequestration. We explored the role of endogenous Li in the brain by depleting it from the diet of wild-type and AD mouse models. Reducing endogenous cortical Li by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice. These findings reveal physiological effects of endogenous Li in the brain and indicate that disruption of Li homeostasis may be an early event in the pathogenesis of AD. Li replacement with amyloid-evading salts is a potential approach to the prevention and treatment of AD.
Article Publication Date: 06/08/2025
DOI: 10.1038/s41586-025-09335-x
