LITHIUM AND ALZHEIMER’S DISEASE: POTENTIAL NEUROPROTECTIVE EFFECTS AND THERAPEUTIC PERSPECTIVES

Dominika Matecka; Weronika Pura; Jakub Mazur; Mateusz Kosowski; Jakub Marciniak; Daniel Chołuj; Karolina Zarówna; Beata Huszcza; Maksymilain Głaz

doi:10.31435/ijitss.3(51).2026.6606

Authors

Dominika Matecka Józef Struś Municipal Hospital, a Multispecialty Medical Centre in Poznań Szwajcarska Street, 61-285 Poznań, Poland https://orcid.org/0009-0000-4644-5943
Weronika Pura The Independent Public Healthcare Institution of the Ministry of the Interior and Administration in Łódź Północna 42 Street, 91–425 Łódź, Poland https://orcid.org/0009-0007-2889-667X
Jakub Mazur Voivodeship Combined Hospital in Kielce 45 Grunwaldzka Street, 25-736 Kielce, Poland https://orcid.org/0009-0005-1089-9210
Mateusz Kosowski Independent Public Healthcare Institution in Koło 25 Księcia Józefa Poniatowskiego Street, 62-600 Koło, Poland https://orcid.org/0009-0001-0811-5326
Jakub Marciniak University Clinical Hospital No. 2 of the Medical University of Łódź 113 Żeromskiego Street, 90-549 Łódź, Poland https://orcid.org/0009-0004-5675-6963
Daniel Chołuj The Independent Public Healthcare Institution of the Ministry of the Interior and Administration in Łódź Północna 42 Street, 91–425 Łódź, Poland https://orcid.org/0009-0009-1445-6336
Karolina Zarówna District Hospital Complex in Oleśnica Armii Krajowej Street, 56-400 Oleśnica, Poland https://orcid.org/0009-0003-6066-7667
Beata Huszcza Dr. Karol Jonscher Municipal Medical Center in Lodz, Milionowa Street 14, 93-113 Łódź, Poland https://orcid.org/0009-0002-2168-5275
Maksymilain Głaz Medical University of Łódź, Łódź, Poland https://orcid.org/0009-0007-5366-3739

DOI:

https://doi.org/10.31435/ijitss.3(51).2026.6606

Keywords:

Lithium, Alzheimer's Disease, Treatment

Abstract

Lithium is an established mood stabilizer whose possible use in Alzheimer’s disease (AD) has emerged from convergent molecular, animal, observational, and early clinical evidence. The principal rationale is that lithium may act on several processes implicated in AD rather than on a single lesion: glycogen synthase kinase-3β (GSK-3β) signaling, tau phosphorylation, amyloid precursor protein processing, neuroinflammation, oxidative and mitochondrial stress, autophagy, neurogenesis, and synaptic plasticity. Animal studies generally report preserved memory and reduced amyloid-related pathology, while small human studies suggest that subtherapeutic lithium may attenuate cognitive decline or modify cerebrospinal-fluid biomarkers. Observational cohorts also associate lithium exposure with lower dementia incidence, but these findings are vulnerable to confounding by indication, comorbidity, treatment adherence, and healthcare use. Evidence is not uniformly positive: a Scottish cohort exposed to extremely low environmental lithium did not support dementia protection, and a recent randomized feasibility trial in mild cognitive impairment found no significant effect on any of six prespecified coprimary outcomes, although one memory measure declined more slowly with lithium. The therapeutic challenge is therefore not simply whether lithium is neuroprotective, but which patients, dose, formulation, exposure duration, and biomarker-defined disease stage are most likely to benefit. Lithium remains an investigational strategy for AD prevention or treatment, not a substitute for established clinical care.

References

A, B., G, F., M, B., M, S., M, F., J, Q., CA, Z., LV, K., E, V., & AF., C. (2024). New advances in the pharmacology and toxicology of lithium: A neurobiologically oriented overview. 323–357. https://doi.org/10.1124/pharmrev.120.000007

Carrillo‐Mora, P., Luna, R., & Colín-Barenque, L. (2014). Amyloid beta: Multiple mechanisms of toxicity and only some protective effects? Oxidative Medicine and Cellular Longevity, 2014, 1–15. https://doi.org/10.1155/2014/795375

Chen, S., Underwood, B. R., Jones, P. B., Lewis, J. R., & Cardinal, R. N. (2022). Association between lithium use and the incidence of dementia and its subtypes: A retrospective cohort study. PLoS Medicine, 19(3), e1003941. https://doi.org/10.1371/journal.pmed.1003941

Damiano, R. F., Loureiro, J. C., Pais, M. V., Pereira, R. F., Menezes Corradi, M. de, Santi, T. D., Bezerra, G. A. M., Radanovic, M., Talib, L. L., & Forlenza, O. V. (2022). Revisiting global cognitive and functional state 13 years after a clinical trial of lithium for mild cognitive impairment. Brazilian Journal of Psychiatry, 45(1), 46–49. https://doi.org/10.47626/1516-4446-2022-2767

Duthie, A. C., Hannah, J., Batty, G. D., Deary, I. J., Starr, J. M., Smıth, D. J., & Russ, T. C. (2023). Low‐level lithium in drinking water and subsequent risk of dementia: Cohort study. International Journal of Geriatric Psychiatry, 38(3), e5890. https://doi.org/10.1002/gps.5890

Forlenza, O. V., Diniz, B. S., Radanovic, M., Santos, F. S., Talib, L. L., & Gattaz, W. F. (2011). Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: Randomised controlled trial. The British Journal of Psychiatry. https://doi.org/10.1192/bjp.bp.110.080044

Forlenza, O. V., Radanovic, M., Talib, L. L., & Gattaz, W. F. (2019). Clinical and biological effects of long-term lithium treatment in older adults with amnestic mild cognitive impairment: Randomised clinical trial. British Journal of Psychiatry. https://doi.org/10.1192/bjp.2019.76

Fraiha-Pegado, J., Paula, V. J. R. D., Alotaibi, T., Forlenza, O. V., & Hájek, T. (2024). Trace lithium levels in drinking water and risk of dementia: A systematic review. International Journal of Bipolar Disorders, 12(1), 32. https://doi.org/10.1186/s40345-024-00348-5

Freland, L., & Beaulieu, J. (2012). Inhibition of GSK3 by lithium, from single molecules to signaling networks. Frontiers in Molecular Neuroscience, 5, 14. https://doi.org/10.3389/fnmol.2012.00014

Gao, L., Zhang, Y., Sterling, K., & Song, W. (2022). Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential. Translational Neurodegeneration. https://doi.org/10.1186/s40035-022-00279-0

Gerhard, T., Devanand, D. P., Huang, C., Crystal, S., & Olfson, M. (2015). Lithium treatment and risk for dementia in adults with bipolar disorder: Population-based cohort study. The British Journal of Psychiatry, 207(1), 46–51. https://doi.org/10.1192/bjp.bp.114.154047

Gildengers, A., Ibrahim, T. S., Anderson, S., Emanuel, J. E., Santini, T., Diaz, J. L., Lopresti, B. J., Royse, S. K., Lopez, O. L., Zeng, X., Almeida, B. de, Alkhateeb, S., Chu, C., Karikari, T. K., Lee, L., Weinstein, A. M., & Butters, M. A. (2026). Low-dose lithium for mild cognitive impairment. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2026.0072

Gildengers, A., Ibrahim, T. S., Zeng, X., Aizenstein, H., Alkhateeb, S., Anderson, S., Chu, C., Diaz, J. L., Emanuel, J. E., Karikari, T. K., Li, J., López, Ó., Lopresti, B. J., Royse, S. K., Sajewski, A., Santini, T., Weinstein, A. M., Wu, M., & Butters, M. A. (2025). The LATTICE study: Design of a pilot feasibility randomized controlled trial of lithium to delay cognitive decline in mild cognitive impairment. Alzheimer s & Dementia Translational Research & Clinical Interventions, 11(2), e70112. https://doi.org/10.1002/trc2.70112

Guilliot, S., Wilson, E. N., Touchon, J., & Soto, M. E. (2024). Nanolithium, a new treatment approach to Alzheimer’s disease: A review of existing evidence and clinical perspectives. The Journal of Prevention of Alzheimer’s Disease. https://doi.org/10.14283/jpad.2024.26

M, G., & M., B. (2024). Lithium: Current state of the art and future directions. https://doi.org/10.1186/s40345-024-00362-7

Manchia, M., Paribello, P., Pinna, M., Steardo, L., Carpiniello, B., Pinna, F., Pisanu, C., Squassina, A., & Hájek, T. (2024). Lithium and its effects: Does dose matter? International Journal of Bipolar Disorders, 12(1), 23. https://doi.org/10.1186/s40345-024-00345-8

Novoa, C., Salazar, P., Cisternas, P., Gherardelli, C., Vera-Salazar, R. F., Zolezzi, J. M., & Inestrosa, N. C. (2022). Inflammation context in Alzheimer’s disease, a relationship intricate to define. Biological Research. https://doi.org/10.1186/s40659-022-00404-3

Nunes, M. A., Schöwe, N. M., Monteiro-Silva, K. C., Baraldi-Tornisielo, T., Souza, S. I. G., Balthazar, J., Albuquerque, M. S., Caetano, A. L., Viel, T. A., & Buck, H. S. (2015). Chronic microdose lithium treatment prevented memory loss and neurohistopathological changes in a transgenic mouse model of Alzheimer’s disease. PLoS ONE, 10(11), e0142267. https://doi.org/10.1371/journal.pone.0142267

Rocha, N. K. R., Themoteo, R., Brentani, H., Forlenza, O., & Paula, V. D. D. (2020). Neuronal–glial interaction in a triple-transgenic mouse model of Alzheimer’s disease: Gene ontology and lithium pathways. Frontiers in Neuroscience. https://doi.org/10.3389/fnins.2020.579984

Rybakowski, J. (2022). Antiviral, immunomodulatory, and neuroprotective effect of lithium. Journal of Integrative Neuroscience, 21(2), 68. https://doi.org/10.31083/j.jin2102068

Shen, Y., Zhao, M., Zhao, P., Meng, L., Zhang, Y., Zhang, G., Taishi, Y., & Sun, L. (2024). Molecular mechanisms and therapeutic potential of lithium in Alzheimer’s disease: Repurposing an old class of drugs. Frontiers in Pharmacology. https://doi.org/10.3389/fphar.2024.1408462

Strawbridge, R., Kerr-Gaffney, J., Bessa, G., Loschi, G., Freitas, H. L. O., Pires, H., Cousins, D., Juruena, M. F., & Young, A. (2022). Identifying the neuropsychiatric health effects of low-dose lithium interventions: A systematic review. Neuroscience and Biobehavioral Reviews. https://doi.org/10.1016/j.neubiorev.2022.104975

Wilson, E. N., Carmo, S. D., Iulita, M. F., Hall, H., Ducatenzeiler, A., Marks, A., Allard, S. T. M., Jia, D., Windheim, J., & Cuello, A. C. (2017). BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology. Translational Psychiatry, 7(8), e1190. https://doi.org/10.1038/tp.2017.169

Zhao, J., Wei, M., Guo, M., Wang, M., Niu, H., Xu, T., & Zhou, Y. (2024). GSK3: A potential target and pending issues for treatment of Alzheimer’s disease. CNS Neuroscience & Therapeutics. https://doi.org/10.1111/cns.14818