Scientists have identified new ways lithium chloride may interact with Alzheimer’s disease mechanisms at the cellular level.
A new study from the University of Eastern Finland (UEF) suggests lithium chloride may influence several cellular processes linked to Alzheimer’s disease.
Alzheimer’s disease (AD) is the most common type of dementia. One of its key features is the abnormal phosphorylation and buildup of Tau proteins inside brain cells, along with the accumulation of β-amyloid (Aβ) plaques.
Researchers have previously used lithium salts, especially lithium chloride and lithium carbonate, in cell and animal models of AD to reduce Tau hyperphosphorylation and aggregation. However, human clinical trials have produced inconsistent results, with some studies showing little or no improvement in cognitive function.
Why Clinical Results Have Been Mixed
A recent US study may help explain those inconsistent findings. Researchers reported that inorganic lithium salts, including lithium chloride and lithium carbonate, can become trapped inside Aβ plaques, limiting their bioavailability. Organic lithium salts may avoid this sequestration, which could improve outcomes in future clinical trials and renew interest in lithium-based treatments for AD.
“This may lead to renewed interest in lithium salts for the prevention and treatment of AD and also underlines the importance of basic research to increase our understanding of disease mechanisms and interactions of drugs used in clinical trials,” says Project Researcher Dorit Hoffmann of the A. I. Virtanen Institute for Molecular Sciences at the University of Eastern Finland.
To better understand lithium’s effects on Alzheimer’s-related pathways, Hoffmann and her colleagues studied two cell-based models of Tau hyperphosphorylation. They examined the effects of lithium chloride using multiple proteomic analysis methods.
New Insights Into Tau Phosphorylation
As expected, lithium chloride treatment reduced Tau phosphorylation at previously identified phosphosites. The researchers also discovered several additional AD-related Tau phosphosites affected by the treatment.
The enzyme GSK-3β, a serine/threonine kinase, is known to be overactive in Alzheimer’s disease and is considered a major driver of abnormal Tau phosphorylation. The new findings suggest lithium chloride may also influence other kinases involved in the disease.
The study further showed that lithium chloride treatment may significantly alter the Rho GTPase signaling pathway. Increased activity of certain Rho GTPases has already been linked to Alzheimer’s disease, although the roles of several others remain unclear.
Researchers Call for Further Investigation
“Our study identified several novel AD-relevant phosphosites affected by lithium chloride treatment and predicts alterations in the activity of multiple kinases and Rho GTPases. The role of these molecules in AD requires further investigation to better understand the impact of lithium compounds on AD pathology and disease mechanisms,” Hoffmann and Research Manager Virpi Aholafrom UEF Bioinformatics Center summarize.
Professors Mikko Hiltunen and Annakaisa Haapasalo also emphasized the need for additional research. “The findings so far indicate that the effects of different lithium salts remain insufficiently understood. More detailed analyses could reveal compounds better suitable for future clinical trials.”
Reference: “Lithium chloride alters Tau phosphorylation, kinase activity, and Rho GTPase signaling in cell models” by Dorit Hoffmann, Virpi Ahola, Nadine Huber, Teemu Natunen, Stina Leskelä, Mari Takalo, Henna Martiskainen, Stephanie Ballweg, Egor Vorontsov, Stefan Selzer, Pekka Kallio, Ian Pike, Jouni Sirviö, Annakaisa Haapasalo and Mikko Hiltunen, 13 April 2026, Biomedicine & Pharmacotherapy.
DOI: 10.1016/j.biopha.2026.119347
The study was part of research projects funded by the Research Council of Finland, Sigrid Jusélius Foundation, Jane and Aatos Erkko Foundation, and the strategic neuroscience funding of the University of Eastern Finland.
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