A 50% reduction in cortical lithium levels in mice was found to markedly increased the deposition of amyloid-beta and the accumulation of phospho-tau, two key hallmarks of Alzheimer's disease pathology, in a recent study published in Nature.

Researchers led by Liviu Aron of the Department of Genetics, Harvard Medical School, Boston, Massachusetts, uncovered a physiological link between endogenous lithium deficiency and the pathogenesis of Alzheimer's Disease (AD). The central finding was that out of 27 metals analyzed in the brains and blood of aged patients, only lithium showed significantly reduced levels in the prefrontal cortex of participants with mild cognitive impairment and AD, as determined by inductively coupled plasma mass spectrometry. This reduction was not observed in the cerebellum, a brain region typically spared from AD pathology.

To investigate this connection further, the researchers utilized mouse models, placing them on a lithium-deficient diet. This dietary intervention successfully reduced cortical lithium levels by approximately 50%. This reduction was shown to markedly increase the deposition of amyloid-beta and the accumulation of phospho-tau, which are defining hallmarks of AD pathology.

Single-nucleus RNA-seq analysis of the mice revealed that lithium deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD. These pathological findings were corroborated by a significant loss of synapses, axons, and myelin, as well as pro-inflammatory microglial activation.

Behaviorally, the lithium-deficient mice exhibited pronounced deficits in learning and memory, which were assessed using standardized tests such as the Morris water-maze, Y-maze, and novel-object recognition tests. The findings present a compelling case that lithium replacement with amyloid-evading salts could be a potential therapeutic avenue for the prevention and treatment of AD.

The authors declare no competing interests.

Source: Nature