by Isabella Colonna
For our Paper of the Month for September, we have chosen Aron L, Ngian ZK, Qiu C, Choi J, Liang M, Drake DM, Hamplova SE, Lacey EK, Roche P, Yuan M, Hazaveh SS, Lee EA, Bennett DA, Yankner BA. Lithium deficiency and the onset of Alzheimer’s disease. Nature. 2025 Aug 6. doi: 10.1038/s41586-025-09335-x. Epub ahead of print. PMID: 40770094.
Several dietary, lifestyle, and environmental factors have been investigated in relation to Alzheimer’s disease (AD), but their contribution to AD pathogenesis remains unclear. Metals are known to play essential roles in brain function; however, the impact of their altered homeostasis in AD has not been fully explored.
In a recent study published in Nature, the authors examined the role of lithium in AD pathogenesis. Using coupled plasma mass spectrometry, they measured metal levels in the prefrontal cortex and cerebellum. Among all the metals analysed, only lithium exhibited decreased concentrations and a reduced cortex-to-serum ratio in the prefrontal cortex—one of the regions most affected by AD—in individuals with AD and mild cognitive impairment (MCI), but not in cognitively healthy older adults. These findings suggest that endogenous lithium homeostasis is disrupted in the brains of individuals with MCI and AD.
Furthermore, in all MCI and AD cases, lithium levels were increased within amyloid plaques compared to plaque-free cortical regions. Reduced lithium levels in non-plaque cortical areas correlated with lower cognitive scores across the entire aging cohort. These observations indicate that amyloid-β (Aβ) deposits sequester lithium, reducing its bioavailability.
In AD mouse models, dietary lithium deficiency led to increased Aβ deposition in the hippocampus, elevated phospho-tau levels, impaired learning and memory, decreased levels of synaptic and myelin proteins, and upregulation of proteins involved in neuroinflammation, lipid metabolism, and mitochondrial membrane organisation. Additionally, lithium deficiency downregulated myelin-related gene expression in oligodendrocytes, reduced myelin-associated protein levels, promoted a reactive pro-inflammatory state, and impaired Aβ clearance.
Importantly, in AD mouse models, lithium replacement therapy using lithium orotate—a lithium salt with reduced amyloid-binding properties—reduced Aβ deposition, phospho-tau accumulation, and neuroinflammation, while improving learning and spatial memory. In wild-type mice, lithium orotate also prevented age-related neuroinflammation, synaptic loss, and cognitive decline.
In conclusion, this study demonstrates that lithium deficiency contributes to Aβ and phospho-tau accumulation, neuroinflammation, and accelerated cognitive decline. Lithium orotate supplementation may help prevent AD-related pathological changes and memory loss, highlighting its potential as a preventive and therapeutic strategy for AD.
