Lithium Deficiency Emerges as Early Trigger in Alzheimer's Pathogenesis, Study Reveals

New research published in Nature reveals that endogenous lithium (Li) depletion—notably in mild cognitive impairment (MCI) and Alzheimer’s disease (AD)—may be a pivotal early event in neurodegeneration. Metallomic analysis of human brains showed Li as the only metal significantly reduced in the prefrontal cortex of MCI and AD patients compared to cognitively normal individuals. Crucially, amyloid-β plaques actively sequester Li, reducing its bioavailability and creating a pathological feedback loop.

"Lithium is dynamically regulated in the brain, and its deficiency directly contributes to cognitive decline during aging. Disruption of Li homeostasis isn't just a consequence—it's a catalyst," states lead researcher Bruce A. Yankner of Harvard Medical School.

Mechanism of Pathology
Mouse models fed Li-deficient diets exhibited:
- ↑ 50-70% amyloid-β deposition and phospho-tau accumulation
- ↑ Microglial activation and pro-inflammatory cytokine release (IL-6, TNF, CCL3/4/5)
- ↓ Synaptic density (PSD-95/synaptophysin) and myelination
- Accelerated memory loss in Morris water maze/Y-maze tests

Single-nucleus RNA-seq revealed transcriptomic shifts in neurons, oligodendrocytes, and microglia overlapping with human AD signatures. The kinase GSK3β was identified as a central mediator: Li deficiency increased GSK3β expression/activity, while its inhibition reversed pathology.

Therapeutic Breakthrough: Lithium Orotate
Conventional lithium carbonate (LiC) binds avidly to amyloid, limiting efficacy. Lithium orotate (LiO) showed:
- ↓ Conductivity (indicating reduced ionization)
- ↓ Amyloid binding affinity (EC~50~ 3.2x higher than LiC for fibrils)
- ↑ Bioavailable Li in non-plaque brain regions

At physiological doses (4.3 µEq/L), LiO: 

• Prevented Aβ/tau pathology in 3xTg/J20 mice  
• Restored synaptic markers and myelin integrity  
• Reversed cognitive deficits without renal/thyroid toxicity

Why This Matters for Tech
- Validates metal homeostasis as a druggable axis in neurodegeneration
- Highlights transcriptomic profiling for identifying early disease mechanisms
- Proposes amyloid-evading compounds as a blueprint for targeted CNS drug delivery

Source: Aron et al. Nature (2025). DOI: 10.1038/s41586-025-09335-x