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It remains the most effective agent for managing acute mania and preventing relapses in bipolar disorder. Despite potential adverse effects, lithium\u2019s use should be carefully considered relative to other treatment options, as these alternatives may present distinct safety and tolerability profiles. The World Health Organization classifies lithium salts as \u2018essential\u2019 medications for inclusion in global healthcare systems. Over the past two decades, the growing recognition of lithium\u2019s efficacy\u2014extending beyond mood stabilization to include reducing suicide risk and inducing neuroprotection\u2014has led to its incorporation into clinical practice guidelines. Current research, particularly from translational models, suggests that lithium\u2019s pleiotropic effects benefit not only mental and brain health but also other organs and systems. This supports its potential as a therapeutic candidate for neurological conditions, particularly those associated with neurodegenerative processes. This article will discuss the historical background, discovery, and early experimentation of lithium in psychiatry. We will also review its mechanisms of action and discuss its potential in the treatment and prevention of neurodegenerative disorders, focusing on Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.3390\/ph18040532","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T05:59:00Z","timestamp":1744091940000},"page":"532","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["An Overview of the Effects of Lithium on Alzheimer\u2019s Disease: A Historical Perspective"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3256-6397","authenticated-orcid":false,"given":"Marcia","family":"Radanovic","sequence":"first","affiliation":[{"name":"Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Hospital das Cl\u00ednicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo (HCFMUSP), S\u00e3o Paulo 05403-010, SP, Brazil"},{"name":"Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBioN), Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico, S\u00e3o Paulo 05403-010, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7019-0485","authenticated-orcid":false,"given":"Monique Patricio","family":"Singulani","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Hospital das Cl\u00ednicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo (HCFMUSP), S\u00e3o Paulo 05403-010, SP, Brazil"},{"name":"Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBioN), Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico, S\u00e3o Paulo 05403-010, SP, Brazil"},{"name":"Centro de Neuroci\u00eancias Translacionais (CNT), Faculdade de Medicina da Universidade de S\u00e3o Paulo (FMUSP), S\u00e3o Paulo 05403-010, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2054-6356","authenticated-orcid":false,"given":"Vanessa de Jesus R.","family":"De Paula","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Hospital das Cl\u00ednicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo (HCFMUSP), S\u00e3o Paulo 05403-010, SP, Brazil"},{"name":"Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBioN), Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico, S\u00e3o Paulo 05403-010, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5866-1993","authenticated-orcid":false,"given":"Leda Leme","family":"Talib","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Hospital das Cl\u00ednicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo (HCFMUSP), S\u00e3o Paulo 05403-010, SP, Brazil"},{"name":"Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBioN), Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico, S\u00e3o Paulo 05403-010, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6962-5899","authenticated-orcid":false,"given":"Orestes Vicente","family":"Forlenza","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, Hospital das Cl\u00ednicas da Faculdade de Medicina da Universidade de S\u00e3o Paulo (HCFMUSP), S\u00e3o Paulo 05403-010, SP, Brazil"},{"name":"Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBioN), Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico, S\u00e3o Paulo 05403-010, SP, Brazil"},{"name":"Centro de Neuroci\u00eancias Translacionais (CNT), Faculdade de Medicina da Universidade de S\u00e3o Paulo (FMUSP), S\u00e3o Paulo 05403-010, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bernard, A. 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