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Lithium deficiency and the onset of Alzheimer's disease.
Nature. 2025 Sep; 645(8081):712-721.Nat

Abstract

The earliest molecular changes in Alzheimer's disease (AD) are poorly understood[1-5]. 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.

Links

Authors+Show Affiliations

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.

Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

Department of Genetics, Harvard Medical School, Boston, MA, USA. bruce_yankner@hms.harvard.edu.

Pub Type(s)

Journal Article

Research Support, N.I.H., Extramural

Language

eng

PubMed ID

40770094

Citation

Aron, Liviu, et al. "Lithium Deficiency and the Onset of Alzheimer's Disease." Nature, vol. 645, no. 8081, 2025, pp. 712-721.

Aron L, Ngian ZK, Qiu C, et al. Lithium deficiency and the onset of Alzheimer's disease. Nature. 2025;645(8081):712-721.

Aron, L., Ngian, Z. K., Qiu, C., Choi, J., Liang, M., Drake, D. M., Hamplova, S. E., Lacey, E. K., Roche, P., Yuan, M., Hazaveh, S. S., Lee, E. A., Bennett, D. A., & Yankner, B. A. (2025). Lithium deficiency and the onset of Alzheimer's disease. Nature, 645(8081), 712-721. https://doi.org/10.1038/s41586-025-09335-x

Aron L, et al. Lithium Deficiency and the Onset of Alzheimer's Disease. Nature. 2025;645(8081):712-721. PubMed PMID: 40770094.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Lithium deficiency and the onset of Alzheimer's disease. AU - Aron,Liviu, AU - Ngian,Zhen Kai, AU - Qiu,Chenxi, AU - Choi,Jaejoon, AU - Liang,Marianna, AU - Drake,Derek M, AU - Hamplova,Sara E, AU - Lacey,Ella K, AU - Roche,Perle, AU - Yuan,Monlan, AU - Hazaveh,Saba S, AU - Lee,Eunjung A, AU - Bennett,David A, AU - Yankner,Bruce A, Y1 - 2025/08/06/ PY - 2024/09/04/received PY - 2025/06/30/accepted PY - 2025/9/18/medline PY - 2025/8/7/pubmed PY - 2025/8/6/entrez SP - 712 EP - 721 JF - Nature JO - Nature VL - 645 IS - 8081 N2 - The earliest molecular changes in Alzheimer's disease (AD) are poorly understood[1-5]. 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. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/40770094/full_citation DB - PRIME DP - Unbound Medicine ER -