Lithium deficiency and the onset of Alzheimer’s disease

Liviu Aron, Zhen Kai Ngian, Chenxi Qiu, Jaejoon Choi, Marianna Liang, Derek M. Drake, Sara E. Hamplova, Ella K. Lacey, Perle Roche, Monlan Yuan, Saba S. Hazaveh, Eunjung A. Lee, David A. Bennett and Bruce A. Yankner ()
Additional contact information
Liviu Aron: Harvard Medical School
Zhen Kai Ngian: Harvard Medical School
Chenxi Qiu: Harvard Medical School
Jaejoon Choi: Harvard Medical School
Marianna Liang: Harvard Medical School
Derek M. Drake: Harvard Medical School
Sara E. Hamplova: Harvard Medical School
Ella K. Lacey: Harvard Medical School
Perle Roche: Harvard Medical School
Monlan Yuan: Harvard Medical School
Saba S. Hazaveh: Harvard Medical School
Eunjung A. Lee: Boston Children’s Hospital
David A. Bennett: Rush University Medical Center
Bruce A. Yankner: Harvard Medical School

Nature, 2025, vol. 645, issue 8081, 712-721

Abstract: Abstract The earliest molecular changes in Alzheimer’s disease (AD) are poorly understood1–5. 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.

Date: 2025
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DOI: 10.1038/s41586-025-09335-x

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