In a groundbreaking new study, researchers have uncovered a pivotal connection between lithium deficiency and the initiation of Alzheimer’s disease (AD), revealing a molecular cascade that implicates microglial cells as central players in the neurodegenerative process. This compelling insight not only deepens the understanding of AD pathogenesis but also points toward novel avenues for intervention in one of the most challenging neurological disorders affecting millions worldwide.
At the crux of the discovery lies the intricate role of microglia, the brain’s resident immune sentinels, whose functional states profoundly influence neuroinflammatory and neurodegenerative dynamics. Single-nucleus RNA sequencing (snRNA-seq) analyses revealed that lithium deficiency precipitates a marked decrease in microglial populations expressing Cx3cr1, a gene encoding a key homeostatic marker. Concurrently, there is an increase in microglia expressing Apoe, a gene intimately associated with AD risk. These transcriptional changes mirror the reactive microglial phenotype observed during AD progression, indicating lithium’s crucial role in maintaining microglial homeostasis.
To gain a more nuanced understanding of microglial alterations under lithium-deficient conditions, investigators isolated viable microglial cells from both transgenic 3xTg and wild-type mouse models. Deep RNA sequencing demonstrated profound transcriptome remodeling in microglia subjected to lithium deficiency, characterized by overlapping gene expression changes across both genetic backgrounds. Genes upregulated in lithium-deficient microglia clustered in pathways linked to Alzheimer’s and broader neurodegenerative processes, encompassing electron transport chain function, respiratory metabolism, amyloid fibril formation, translation, and oxidative stress responses.
Conversely, genes downregulated by lithium deficiency were enriched for biological processes critical to genomic and proteomic integrity, such as DNA damage responses, cellular stress adaptation, intracellular import mechanisms, and protein catabolism. This dichotomous gene regulation profile suggests that lithium shortage may impair essential microglial housekeeping functions while simultaneously exacerbating pathological activation, tipping the balance toward neurodegeneration.
Further analysis connected lithium deficiency-induced transcriptomic signatures to established genetic risk factors for Alzheimer’s disease identified through genome-wide association studies (GWAS). Notable risk genes such as Trem2, Bin1, Clu, Picalm, Cd33, HLA-DRB1 orthologue H2-Eb1, Inpp5d, Abca1, Abca7, and Adam10 were among those significantly enriched in lithium-deprived microglia. Strikingly, there was also a strong overlap with gene sets characteristic of microglia expressing glycoprotein NMB (GPNMB), a marker of microglial populations expanding during AD progression. Upregulation of GPNMB expression further validated the transition to a reactive and potentially neurotoxic microglial state under lithium-deficient conditions.
Immunohistochemical examination revealed that lithium deficiency robustly increased microglial activation markers. Specifically, the density of CD68-positive microglia—a hallmark of reactive, phagocytic microglia—was elevated in the hippocampi of 3xTg AD mice subjected to a lithium-deficient diet. This microglial activation was similarly noted in a separate AD mouse model (J20), underscoring the reproducibility and robustness of the phenomenon. The study also identified enhanced expression of microglial proteins GPNMB and lipoprotein lipase (LPL), both implicated in AD-associated microglial phenotypes, strengthening the link between lithium deficiency and microglial pathology.
Functionally, microglia isolated from lithium-deficient mice exhibited heightened pro-inflammatory responses when challenged ex vivo with lipopolysaccharide (LPS). These cells secreted elevated levels of classical pro-inflammatory cytokines including interleukin-6 (IL-6), tumor necrosis factor (TNF), and granulocyte-colony stimulating factor (G-CSF), alongside chemokines such as CCL3, CCL4, CCL5, and CXCL2. This cytokine milieu fosters a neurotoxic and inflammatory environment, which may potentiate neuronal dysfunction and amyloid pathology in the Alzheimer’s brain.
In addition to heightened inflammatory activity, lithium deficiency significantly impaired the microglial capacity for amyloid-beta 42 (Aβ42) peptide uptake and degradation. These functions are critical for clearing amyloid plaques, the classic pathological hallmark of AD. The diminished phagocytic and catabolic efficiency of microglia under lithium-deficient conditions aligns with a scenario wherein clearance of pathogenic protein aggregates is compromised, thus accelerating disease progression.
An intriguing mechanistic link tying these findings together involves glycogen synthase kinase 3 beta (GSK3β), a kinase known to modulate multiple aspects of neurodegeneration and inflammation. Immunolabelling demonstrated increased GSK3β levels in microglia from lithium-deficient mice. Pharmacological inhibition of GSK3β restored Aβ42 uptake and degradation capabilities in cultured microglia from lithium-deficient animals, highlighting GSK3β as a critical modulator in lithium’s regulation of microglial function and suggesting potential therapeutic targets.
The converging evidence from transcriptomics, immunohistochemistry, cytokine secretion profiles, and functional assays paints a comprehensive picture of lithium as a vital regulator of microglial state and activity. Lithium deficiency mobilizes microglia into a reactive, pro-inflammatory, and functionally compromised phenotype that mirrors features observed in Alzheimer’s disease, thus implicating systemic lithium status in AD pathogenesis.
These findings carry profound implications for public health and clinical strategies. Given the widespread prevalence of suboptimal lithium exposure in the general population, subtle lithium insufficiency could represent a modifiable risk factor accelerating neurodegeneration. The results prompt a reevaluation of nutritional and environmental lithium intake and its integration into preventive approaches targeting early stages of Alzheimer’s disease.
While lithium has been historically utilized in psychiatric medicine, primarily for bipolar disorder, this study rejuvenates interest in its neuroprotective properties and advocates for its further exploration as a potential disease-modifying agent in neurodegenerative diseases. Careful determination of optimal dosages and assessment of long-term safety profiles will be essential steps to harness lithium’s therapeutic potential fully.
This pioneering research adds a novel dimension to the complex landscape of Alzheimer’s pathology, bridging metabolic, inflammatory, and genetic factors through the common denominator of lithium status. As the global burden of Alzheimer’s continues to grow, these insights chart a promising course toward innovative, biologically grounded interventions that may delay or halt the progression of this devastating disorder.
In summary, lithium deficiency exerts a profound impact on microglial biology, driving transcriptional reprogramming toward a disease-associated state characterized by impaired amyloid clearance and amplified neuroinflammation. The link to key AD genetic risk pathways and functional impairments underscores lithium’s foundational role in brain homeostasis and neurodegenerative disease modulation. Further research will be essential to translate these compelling findings into clinical benefits for patients at risk of Alzheimer’s disease.
Subject of Research: Lithium deficiency and its impact on microglial activation and Alzheimer’s disease onset
Article Title: Lithium deficiency and the onset of Alzheimer’s disease
Article References:
Aron, L., Ngian, Z.K., Qiu, C. et al. Lithium deficiency and the onset of Alzheimer’s disease. Nature (2025). https://doi.org/10.1038/s41586-025-09335-x
Image Credits: AI Generated
